NCBI Conserved Domain Search

Tick anticoagulant peptide, and similar proteins; Tick anticoagulant peptide (TAP) is a competitive inhibitor of factor Xa, a serine protease that converts prothrombin into thrombin, which acts to convert fibrinogen into fibrin, the insoluble matrix of blood clots. TAP is one of the antihemostatic components evolved in the blood-feeding tick. This subfamily also includes the N-terminal Kunitz inhibitor domain of ornithodorin which binds to the active site of thrombin, while the C-terminal domain binds at the fibrinogen recognition exosite. The TAP structure is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438634 Cd Length: 60 Bit Score: 78.76 E-value: 8.31e-18

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872  219 HNSCDLKFEPVLREECISADWAEKFFWNSeFKDCEPFWYdssCDPRDRaGKNFFETFEDCKNKCD 283
Cdd:cd21630      1 NRLCDKPRGPDLTEECDSEAWERRYFRNG-KGGCESFWY---CDEEDT-GANYFSSMEDCFNACF 60

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 77.20 E-value: 2.28e-17

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd00109      1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 74.99 E-value: 1.89e-16

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872  1343 FRCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:smart00131    1 DVCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 73.06 E-value: 7.10e-16

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1344 RCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:pfam00014    1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 72.97 E-value: 7.63e-16

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd00109      1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 70.93 E-value: 4.19e-15

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22595      4 CKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 70.75 E-value: 5.04e-15

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:pfam00014    1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 70.66 E-value: 5.21e-15

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd00109      1 CLLPPDPGP-CRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 68.05 E-value: 5.09e-14

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1608 PCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:pfam00014    1 ICSLPPDSGP-CKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 67.29 E-value: 7.94e-14

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872  1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:smart00131    2 VCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 66.16 E-value: 2.08e-13

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22615      4 CLSPKDEGLCSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 65.73 E-value: 3.21e-13

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1344 RCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22627      2 PCLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 65.36 E-value: 3.71e-13

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872  1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:smart00131    1 DVCLLPPDTGP-CGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 65.53 E-value: 3.80e-13

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKACE 1602
Cdd:cd22632      1 PSLCQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTCK 55

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 65.26 E-value: 4.51e-13

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGYGKNedsclpqAGFRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd00109      1 CLLPPDPGPCRA-------YFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 64.98 E-value: 5.54e-13

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 1972288872  1407 DCHLPMHIGYGKNEDSclpqagfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:smart00131    2 VCLLPPDTGPCGGSIP-------RYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 64.17 E-value: 9.52e-13

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22631      1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 63.47 E-value: 1.76e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22608      4 CYLPADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 63.31 E-value: 2.49e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1344 RCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22624      1 RCTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETC 52

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 63.04 E-value: 2.53e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGYGKnedsclpQAGFRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:pfam00014    2 CSLPPDSGPCK-------ASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 63.03 E-value: 3.36e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22616      5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 62.25 E-value: 4.12e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22631      1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 62.17 E-value: 5.56e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22633      5 CLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 61.62 E-value: 8.18e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22629      2 ICKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 61.46 E-value: 9.11e-12

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22630      2 ACSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 61.18 E-value: 1.21e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22594      5 CELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 61.05 E-value: 1.42e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22639      1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 60.83 E-value: 1.52e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22637      1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 60.79 E-value: 1.73e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22594      2 PKFCELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 60.35 E-value: 2.03e-11

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22635     17 RWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 60.52 E-value: 2.10e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22603      3 CLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 60.38 E-value: 2.20e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22615      4 CLSPKDEGL-CSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 59.71 E-value: 3.74e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22638      1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 59.58 E-value: 3.83e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1484 VCFEPPgDRGICGKNSstnplKRWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:pfam00014    1 ICSLPP-DSGPCKASI-----PRWYYnpTTGTCEPFTYGGCGGNANNFESLEECESTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 59.59 E-value: 4.96e-11

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 1972288872  1483 EVCFEPPgDRGICGKNSStnplkRWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:smart00131    1 DVCLLPP-DTGPCGGSIP-----RYYYdpETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 59.10 E-value: 5.47e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1485 CFEPPgDRGICgknssTNPLKRWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd00109      1 CLLPP-DPGPC-----RAYFPRWYYnsETGQCEEFIYGGCGGNANNFETKEECEATC 51

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 59.29 E-value: 6.14e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1549 RICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22613      2 SFCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 59.09 E-value: 7.17e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22618      2 CSEPKVVGPCKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 58.81 E-value: 8.80e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1551 CSFSPDWGS-CNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22635      1 CLLDKDAGTvCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 58.53 E-value: 9.99e-11

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22605      2 CLKEPDREDCGEEQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 58.17 E-value: 1.20e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22638      1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 58.30 E-value: 1.37e-10

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1485 CFEPPgDRGICgKNSSTnplkRWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTCNGLMNSN 1546
Cdd:cd22624      2 CTEPP-VTGPC-RASFT----RWYYdpLSRKCHRFTYGGCDGNENNFETEDECMETCSGVTEKD 59

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 58.16 E-value: 1.53e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22617      1 PKVCREVPDEGPCRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 58.02 E-value: 1.61e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1547 DPRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22616      1 NAEICLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 57.87 E-value: 1.92e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22599      5 ICRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKAC 56

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 57.82 E-value: 2.01e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22600      2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELAC 52

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 57.62 E-value: 2.17e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22593      1 CSLPLDEGSGNSSLTRWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 57.36 E-value: 2.59e-10

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22613     13 CKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 57.14 E-value: 3.18e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972288872 1345 CLEPVEI-----GSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22634      2 CGQPHSLgggdgISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 56.99 E-value: 3.85e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22629      3 CKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 56.69 E-value: 4.74e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1549 RICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22604      4 KQCSPTADSGPCFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 56.49 E-value: 5.00e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22627      2 PCLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 56.08 E-value: 7.96e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGYGKNEDSclpqagfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22593      1 CSLPLDEGSGNSSLT-------RWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 56.16 E-value: 8.51e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKCE 1661
Cdd:cd22614      3 DFCFLEEDPGI-CRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTCE 56

Tick anticoagulant peptide, and similar proteins; Tick anticoagulant peptide (TAP) is a competitive inhibitor of factor Xa, a serine protease that converts prothrombin into thrombin, which acts to convert fibrinogen into fibrin, the insoluble matrix of blood clots. TAP is one of the antihemostatic components evolved in the blood-feeding tick. This subfamily also includes the N-terminal Kunitz inhibitor domain of ornithodorin which binds to the active site of thrombin, while the C-terminal domain binds at the fibrinogen recognition exosite. The TAP structure is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438634 Cd Length: 60 Bit Score: 56.03 E-value: 8.74e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1972288872  668 DLCDEPLHPKLEEDCKNDQWEIQWFFNsDRGACKSFWYGGCEIESRNFFPDHANCRHSC 726
Cdd:cd21630      2 RLCDKPRGPDLTEECDSEAWERRYFRN-GKGGCESFWYCDEEDTGANYFSSMEDCFNAC 59

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 55.75 E-value: 9.02e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22628      1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 55.69 E-value: 1.07e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSWCEAMSnRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22593      1 CSLPLDEGSGNSSLT-RWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 55.56 E-value: 1.25e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22599      6 CRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKAC 56

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 55.44 E-value: 1.33e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22637      1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 55.49 E-value: 1.38e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKACE 1602
Cdd:cd22611      2 VCSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNICK 54

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 55.23 E-value: 1.41e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22633      2 NSICLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 55.35 E-value: 1.47e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSWCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22635      1 CLLDKDAGTVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 54.96 E-value: 1.59e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1345 CLEPVEIGS-CQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22635      1 CLLDKDAGTvCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 55.21 E-value: 1.60e-09

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 1972288872 1554 SPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22634     10 GGDGISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 55.22 E-value: 1.66e-09

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972288872 1551 CSFSPDWGSC--NQLRyvWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKACE-VTGTD 1607
Cdd:cd22624      2 CTEPPVTGPCraSFTR--WYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCSgVTEKD 59

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 55.14 E-value: 1.75e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22595      1 PKFCKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 54.56 E-value: 2.32e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22627      1 DPCLLPMDEGS-CSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 54.94 E-value: 2.35e-09

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCS 1466
Cdd:cd22616     20 RYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTCW 56

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 54.53 E-value: 2.45e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22630      3 CSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 54.43 E-value: 3.06e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22601      3 VCDLPADRGPCTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANC 54

Calcium-binding EGF-like domain;

Pssm-ID: 214542 [Multi-domain] Cd Length: 39 Bit Score: 53.79 E-value: 3.46e-09

                            10        20        30
                    ....*....|....*....|....*....|....*....
gi 1972288872    13 DLNECDNGAVCGPNARCVNEIGSFQCVCDAGFSTDGDCK 51
Cdd:smart00179    1 DIDECASGNPCQNGGTCVNTVGSYRCECPPGYTDGRNCE 39

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 54.12 E-value: 3.52e-09

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22639     16 KWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 53.51 E-value: 5.78e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22606      1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 53.46 E-value: 6.75e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22608      1 PKFCYLPADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 53.70 E-value: 6.90e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972288872 1340 ESKFRCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22623      1 QSELYCLAPKKVGPCRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSAC 56

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 53.07 E-value: 9.89e-09

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTrgTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22598      2 TCRLPSDRGRCKASFERWYFNGR--TCAKFIYGGCGGNDNKFPTQEACMKRC 51

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 52.83 E-value: 1.19e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1972288872 1558 GSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22609      9 GVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 52.81 E-value: 1.22e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22607      1 VCSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 52.61 E-value: 1.32e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1972288872 1501 TNPLKRWTYGNQK--CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22593     11 NSSLTRWYYDPKKgqCKPFTYKGKGGNENNFLTKEDCEETC 51

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 52.28 E-value: 1.36e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22628      1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 52.48 E-value: 1.37e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1344 RCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22621      2 FCHLPKVVGRCRASFPRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 52.43 E-value: 1.48e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22632      4 CQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTC 54

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 52.29 E-value: 1.62e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972288872 1548 PRICSFSPDWGSC--NQLRYvwFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22615      1 PSFCLSPKDEGLCsaSVTRY--YYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 52.43 E-value: 1.63e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22603     12 CKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 52.19 E-value: 1.74e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22639      1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 52.15 E-value: 1.79e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22633     14 CRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 51.77 E-value: 2.41e-08

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972288872 1407 DCHLPMHIGYGKnedsclpqAGF-RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22633      4 ICLLPKDVGGCR--------ARFpRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 51.54 E-value: 3.22e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22614      5 CFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTC 55

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 51.40 E-value: 3.42e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1201 CLQPFDTTyetSCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd00109      1 CLLPPDPG---PCRAYFPR--WYYNSETGQCEEFIYGGCGG-NANNFETKEECEATC 51

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 51.32 E-value: 3.74e-08

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1972288872 1567 WFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22621     19 WWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 51.11 E-value: 3.93e-08

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872  1200 ACLQPFDTTYetsCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:smart00131    2 VCLLPPDTGP---CGGSIPR--YYYDPETGTCEPFTYGGCGG-NANNFESLEECERTC 53

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 51.20 E-value: 4.45e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22613      4 CAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 51.11 E-value: 4.48e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1485 CFEPPGDRGICGKNSStnplkRWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22635      1 CLLDKDAGTVCGDYVQ-----RWYYdpATGACNRFWYGGCGGNANRFATEAECLRTC 52

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 50.89 E-value: 4.60e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22603      3 CLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 51.14 E-value: 4.72e-08

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22615     19 RYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 50.69 E-value: 5.66e-08

                           10        20
                   ....*....|....*....|....*....
gi 1972288872 1511 NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22631     23 QGRCSRFWYGGCGGNANRFETQEECENLC 51

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 50.52 E-value: 5.95e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22609      2 CLEPKVVGVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 50.45 E-value: 7.18e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1489 PGDRGICGKNsstnpLKRWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22629      6 PKDEGTCRDF-----VLKWYYDpeTKSCARFWYGGCGGNENRFDSQEECEKVC 53

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 50.15 E-value: 8.18e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22626      1 CSLELDYGVGKAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 50.39 E-value: 8.20e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22594     14 CNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 50.64 E-value: 8.57e-08

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22620      3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKEC 53

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 49.95 E-value: 9.95e-08

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22592     11 CKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 50.20 E-value: 1.01e-07

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872 1504 LKRWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22634     20 IPSWSYNpdKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 49.97 E-value: 1.04e-07

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22628     16 KWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 49.74 E-value: 1.23e-07

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22603     18 RYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

Pssm-ID: 238011 Cd Length: 38 Bit Score: 49.17 E-value: 1.41e-07

                           10        20        30
                   ....*....|....*....|....*....|...
gi 1972288872   13 DLNECDNGAVCGPNARCVNEIGSFQCVCDAGFS 45
Cdd:cd00054      1 DIDECASGNPCQNGGTCVNTVGSYRCSCPPGYT 33

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 49.53 E-value: 1.50e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22593      1 CSLPLDEGSGNSSLTRWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 49.37 E-value: 1.52e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22609      2 CLEPKVVGV-CKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 49.57 E-value: 1.63e-07

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872  1072 SLSKPCGDGKSWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:smart00131    4 LLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGC-GGNANNFESLEECERTC 53

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 49.28 E-value: 1.73e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22622      3 CAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 49.31 E-value: 1.90e-07

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22638     16 KWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 49.23 E-value: 1.97e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1548 PRICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKACE 1602
Cdd:cd22614      2 PDFCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTCE 56

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 49.18 E-value: 2.03e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1200 ACLQPFDTTyetSCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:pfam00014    1 ICSLPPDSG---PCKASIPR--WYYNPTTGTCEPFTYGGCGG-NANNFESLEECESTC 52

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 49.31 E-value: 2.08e-07

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22638     10 CRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 49.29 E-value: 2.11e-07

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972288872 1408 CHLPMHIGygknedSClpqAGF--RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22629      3 CKLPKDEG------TC---RDFvlKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 49.36 E-value: 2.26e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22595      4 CKLPVRPGP-CKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 49.11 E-value: 2.31e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1489 PGDRGICGKNSStnplkRW----TYGnqKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22639      4 PKDRGPCRNYTV-----KWyfdmAYG--GCSRFWYGGCGGNGNRFDTEEECKAVC 51

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 49.24 E-value: 2.43e-07

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872 1429 FRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCS 1466
Cdd:cd22594     19 PAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTCA 56

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 48.77 E-value: 2.72e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22616      5 CLLPPDEGP-CRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 49.10 E-value: 2.83e-07

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1406 VDCHLPMHIGYGKnedsclpqAGF-RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCSQ 1467
Cdd:cd22620      1 KDCQLPSDTGRGK--------ASFtRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKECAQ 55

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 48.79 E-value: 2.91e-07

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1078 GDGKSWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:pfam00014    9 GPCKASIPRWYYNPTTGTCEPFTYGGC-GGNANNFESLEECESTC 52

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 48.96 E-value: 2.93e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22600      2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELAC 52

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 48.53 E-value: 3.23e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22617      4 CREVPDEGP-CRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 48.45 E-value: 3.30e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGygknedSCLPQAGfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22608      4 CYLPADPG------PCKAYIP-RFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 48.69 E-value: 3.51e-07

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1567 WFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKACE 1602
Cdd:cd22623     22 WHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSACR 57

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 48.62 E-value: 3.54e-07

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22599     21 RFYFNTETGQCTEFIYGGCGGNENNFETIEECEKAC 56

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 48.65 E-value: 3.68e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22601      4 CDLPADRGPCTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANC 54

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 48.58 E-value: 3.89e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22607      2 CSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 48.40 E-value: 3.91e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1551 CSFSPDWGSC--NQLRYvwFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22596      3 CKLPPDAGPCfgMIQRY--FYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 48.55 E-value: 4.03e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22611      3 CSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNIC 53

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 47.92 E-value: 4.89e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22602      1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 48.03 E-value: 5.20e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1201 CLQPFDTTyeTSCSAEkpQQYYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22635      1 CLLDKDAG--TVCGDY--VQRWYYDPATGACNRFWYGGCGG-NANRFATEAECLRTC 52

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 48.06 E-value: 5.23e-07

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22608     13 CKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 54

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 48.24 E-value: 5.30e-07

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22599     15 CRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKAC 56

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 48.02 E-value: 5.42e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22592      2 CLEPPYTGPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 47.85 E-value: 5.44e-07

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22621     12 CRASFPRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 48.00 E-value: 5.50e-07

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1481 SSEVCFEPPgDRGICgknssTNPLKRWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22616      1 NAEICLLPP-DEGPC-----RALIPRYYYDryTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Kunitz-type serine protease inhibitor subunit of beta 2-bungarotoxin, and similar proteins; This model includes the Kunitz inhibitor subunit of beta 2-bungarotoxin, a presynaptic neurotoxin of the Bungarus multicinctus venom. Beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to the Kunitz protease inhibitor subunit; the latter subunit is homologous to venom basic protease inhibitors but has no protease inhibitor activity and is non-toxic. The beta-bungarotoxin Kunitz subunit serves to guide the toxin to its site of action on the presynaptic membrane by virtue of a high-affinity interaction with a specific subclass of voltage-sensitive potassium channels. This subfamily also includes Kunitz-type serine protease inhibitor homolog beta-bungarotoxin B1 chain and protease inhibitor-like protein 1 (PILP-1). The B1 chain also has no protease inhibitor activity but blocks voltage-gated potassium channels, while PILP-1 inhibits trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438662 Cd Length: 58 Bit Score: 47.94 E-value: 7.61e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22619      7 CDKPPDTKRCKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 47.35 E-value: 8.39e-07

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1506 RWTYGN--QKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22606     17 RWAYNSllKQCQSFVYGGCEGNENNFESKEACEDAC 52

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 47.56 E-value: 9.85e-07

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22620      3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKEC 53

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 47.31 E-value: 1.17e-06

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCS 1466
Cdd:cd22614     20 RYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTCE 56

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 46.91 E-value: 1.23e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1489 PGDRGICGKNsstnpLKRWTYGNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22598      6 PSDRGRCKAS-----FERWYFNGRTCAKFIYGGCGGNDNKFPTQEACMKRC 51

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 47.18 E-value: 1.39e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22620     12 GKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKEC 53

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 46.97 E-value: 1.41e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22622     12 CRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 46.58 E-value: 1.73e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22606      2 CSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 46.73 E-value: 1.80e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22601      2 DVCDLPADRGP-CTAYIPRWFYNKTTKKCEKFVYGGCQGNKNRFETKDDCLANC 54

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 46.61 E-value: 1.82e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1344 RCLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22617      3 VCREVPDEGPCRALITRYFYNMTSMRCEEFTYGGCYGNGNNFRDKSSCISAC 54

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 46.48 E-value: 1.86e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22596      1 DSCKLPPDAGP-CFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

first Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the first Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438644 Cd Length: 55 Bit Score: 46.34 E-value: 2.11e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1489 PGDRGICgknssTNPLKRWTYGNQ--KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22601      7 PADRGPC-----TAYIPRWFYNKTtkKCEKFVYGGCQGNKNRFETKDDCLANC 54

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 46.44 E-value: 2.20e-06

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1506 RWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22630     18 KWYYdqEQKECSQFWYGGCGGNKNRFETQEECEALC 53

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 46.35 E-value: 2.21e-06

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1596 ICQKAcevtgtdPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22634      1 ICGQP-------HSLGGGDGIS-CFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Calcium-binding EGF domain;

Pssm-ID: 429571 Cd Length: 32 Bit Score: 45.69 E-value: 2.23e-06

                           10        20        30
                   ....*....|....*....|....*....|..
gi 1972288872   13 DLNECDNG-AVCGPNARCVNEIGSFQCVCDAG 43
Cdd:pfam07645    1 DVDECATGtHNCPANTVCVNTIGSFECRCPDG 32

Kunitz-type serine protease inhibitor subunit of beta 2-bungarotoxin, and similar proteins; This model includes the Kunitz inhibitor subunit of beta 2-bungarotoxin, a presynaptic neurotoxin of the Bungarus multicinctus venom. Beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to the Kunitz protease inhibitor subunit; the latter subunit is homologous to venom basic protease inhibitors but has no protease inhibitor activity and is non-toxic. The beta-bungarotoxin Kunitz subunit serves to guide the toxin to its site of action on the presynaptic membrane by virtue of a high-affinity interaction with a specific subclass of voltage-sensitive potassium channels. This subfamily also includes Kunitz-type serine protease inhibitor homolog beta-bungarotoxin B1 chain and protease inhibitor-like protein 1 (PILP-1). The B1 chain also has no protease inhibitor activity but blocks voltage-gated potassium channels, while PILP-1 inhibits trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438662 Cd Length: 58 Bit Score: 46.40 E-value: 2.26e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22619      7 CDKPPDTKRCKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 46.19 E-value: 2.28e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22637      1 CDQPKDTGP-CDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 46.09 E-value: 2.59e-06

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1506 RWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22627     18 LWYYhqKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 46.07 E-value: 2.59e-06

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1429 FRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22631     15 MMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 46.10 E-value: 2.79e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1972288872 1558 GSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22592      9 GPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 46.13 E-value: 2.87e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1488 PPGDRGICGKNsstnpLKRWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22615      6 SPKDEGLCSAS-----VTRYYYNsaTKTCEPFNYTGCGGNNNNFTSKKDCLRVC 54

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 45.89 E-value: 3.01e-06

                           10        20
                   ....*....|....*....|....*....
gi 1972288872 1513 KCTSFTYSGCGGNRNRFATQDICENTCNG 1541
Cdd:cd22595     28 KCHPFTYSGCGGNANRFKTIEECRRTCVG 56

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 45.46 E-value: 3.79e-06

                           10        20        30
                   ....*....|....*....|....*....|.
gi 1972288872 1509 YGNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22638     21 PSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 45.72 E-value: 3.81e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1972288872  932 WVVRSYYDSKAEKCKAFWYGGCHTSSRNiwFDKET-CRTSC 971
Cdd:cd22635     14 YVQRWYYDPATGACNRFWYGGCGGNANR--FATEAeCLRTC 52

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 45.43 E-value: 3.96e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22622      3 CAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 45.61 E-value: 4.15e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22602      1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438637 Cd Length: 56 Bit Score: 45.38 E-value: 4.66e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972288872 1487 EPPGDRGICgknsstNPLKRWTYGN---QKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22594      6 ELPADPGPC------NAYKPAFYYNpasHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 45.42 E-value: 4.71e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872  670 CDEPLHPKleeDCknDQWEIQWFFNSDRGACKSFWYGGCEIESrNFFPDHANCRHSC 726
Cdd:cd22637      1 CDQPKDTG---PC--DNWVLKWYYDSKKGSCRQFYYGGCGGND-NRFDTEEECEARC 51

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 45.33 E-value: 4.73e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872  685 DQWEIQWFFNSDRGACKSFWYGGCEIESRNFFPDHAnCRHSC 726
Cdd:cd22635     12 GDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAE-CLRTC 52

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 45.43 E-value: 5.11e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22606     11 CKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 45.26 E-value: 5.37e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872  675 HPKLEEDCKNdqWEIQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd22639      3 LPKDRGPCRN--YTVKWYFDMAYGGCSRFWYGGCG-GNGNRFDTEEECKAVC 51

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 45.04 E-value: 6.53e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22605      2 CLKEPDREDCGEEQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 45.09 E-value: 6.67e-06

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872 1504 LKRWTYGNQK--CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22611     16 FPRWWYDKETntCSKFIYGGCQGNNNNFQSEAICQNIC 53

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 45.23 E-value: 6.71e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKCE 1661
Cdd:cd22623     15 CRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSACR 57

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 44.72 E-value: 7.10e-06

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22607     17 RWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 44.65 E-value: 7.82e-06

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22613     19 RFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

Kunitz-type domain 1 (K1) of Ixolaris, and similar proteins; This model includes the first Kunitz-type domain (K1) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. While K2 is an extraordinarily dynamic domain that encompasses several residues involved in FX binding, K1 domain keeps as a rigid platform supporting the conformational dynamic of the K2 domain, forming a salt bridge with FXa. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438668 Cd Length: 53 Bit Score: 44.56 E-value: 8.22e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1609 CMESLDRGSWCEAM-SNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22625      1 CTLPIQEITTCESQpTKRYGYNKKTQQCEEFLGTECGGGGNSFEEAKECWSSC 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 44.55 E-value: 9.03e-06

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 1972288872   76 EIKYYYDADSVQCKQFFYGGCKTTSRNfFADLQTCDVICV 115
Cdd:pfam00014   15 IPRWYYNPTTGTCEPFTYGGCGGNANN-FESLEECESTCR 53

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 44.61 E-value: 9.40e-06

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872 1086 RYFYDKDTRSCRMFWSNGCFsSSKNNFDDLETCQWKCE 1123
Cdd:cd22614     20 RYFYNNQSKQCERFKYGGCL-GNQNNFESLEECQNTCE 56

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 44.68 E-value: 9.51e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22597      4 CRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYC 54

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 44.60 E-value: 9.55e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDraSRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22598      3 CRLPSDRGRCKASFERWYFN--GRTCAKFIYGGCGGNDNKFPTQEACMKRC 51

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 44.34 E-value: 1.02e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1485 CFEPPGdRGICGKNsstnpLKRWTYGNQK--CTSFTYSGCGGNRNRFATQDICENTCN 1540
Cdd:cd22632      4 CQLPPA-RGPCRSN-----ILRYFYNSTSreCEPFIYGGCNGNANNFETVEMCLRTCK 55

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 44.43 E-value: 1.08e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKCE 1661
Cdd:cd22624      2 CTEPPVTGP-CRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCS 53

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 44.52 E-value: 1.11e-05

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22630     18 KWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 44.27 E-value: 1.15e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1485 CFEPPgDRGICGKNSStnplkRWTYGNQK--CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22605      2 CLKEP-DREDCGEEQV-----RWYFDAKRgnCFTFTYGGCDGNRNHFETYEECRLAC 52

Tick anticoagulant peptide, and similar proteins; Tick anticoagulant peptide (TAP) is a competitive inhibitor of factor Xa, a serine protease that converts prothrombin into thrombin, which acts to convert fibrinogen into fibrin, the insoluble matrix of blood clots. TAP is one of the antihemostatic components evolved in the blood-feeding tick. This subfamily also includes the N-terminal Kunitz inhibitor domain of ornithodorin which binds to the active site of thrombin, while the C-terminal domain binds at the fibrinogen recognition exosite. The TAP structure is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438634 Cd Length: 60 Bit Score: 44.48 E-value: 1.17e-05

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1972288872  426 CDLEYDDALRNECTSADWTELYYWNAqFKECEAFWYdssCgDQDFSKKNLFKNFDDCNNQC 486
Cdd:cd21630      4 CDKPRGPDLTEECDSEAWERRYFRNG-KGGCESFWY---C-DEEDTGANYFSSMEDCFNAC 59

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 44.14 E-value: 1.19e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22631      1 CLLGQDAGS-CQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 44.46 E-value: 1.27e-05

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872 1506 RWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTCNG 1541
Cdd:cd22623     21 RWHYnaASGKCEEFVFGGCKGNKNNYLSEEECLSACRG 58

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 43.96 E-value: 1.30e-05

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22600     17 RWFFNVTTGACETFVYGGCGGNANNYKSQEECELAC 52

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 43.72 E-value: 1.48e-05

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1221 YYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22639     16 KWYFDMAYGGCSRFWYGGCGG-NGNRFDTEEECKAVC 51

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438667 Cd Length: 61 Bit Score: 44.05 E-value: 1.56e-05

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCS 1466
Cdd:cd22624     17 RWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCS 53

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 43.96 E-value: 1.64e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22600      2 CKPAAESGL-CAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELAC 52

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 43.68 E-value: 1.71e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1550 ICSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKAC 1601
Cdd:cd22618      1 ICSEPKVVGPCKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 43.96 E-value: 1.76e-05

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22632     19 RYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTC 54

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 43.81 E-value: 1.78e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1485 CFEPPgDRGICGknsstNPLKRWTYGNQ--KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22628      1 CLEPL-DPGPCR-----EYVVKWYYDKQanSCAQFWYGGCEGNRNRFETEEECRKTC 51

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 43.68 E-value: 1.78e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1213 CSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22618     11 CKAYFPR--FYFDSETGKCTPFIYGGCGG-NGNNFETLHACRAIC 52

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 43.42 E-value: 1.85e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22628      1 CLEPLDPGP-CREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 43.60 E-value: 1.86e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22626      1 CSLELDYGVGKAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438643 Cd Length: 54 Bit Score: 43.57 E-value: 1.90e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1972288872 1487 EPPGDRGICgknssTNPLKRWTYGNQ--KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22600      3 KPAAESGLC-----AAYLERWFFNVTtgACETFVYGGCGGNANNYKSQEECELAC 52

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 43.44 E-value: 2.18e-05

                           10        20
                   ....*....|....*....|....*..
gi 1972288872 1513 KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22608     28 KCQQFIYGGCKGNANNFETKDECRYTC 54

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 43.53 E-value: 2.35e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1551 CSFSPDWGSCNQLRYVWFYNLTRGTCDQFLYGGCGGNPNRFDTFEICQKACE 1602
Cdd:cd22597      4 CRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYCG 55

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438670 Cd Length: 53 Bit Score: 43.39 E-value: 2.38e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMhigygkNEDSCLPQAgFRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22627      3 CLLPM------DEGSCSDYT-LLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 43.04 E-value: 2.69e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1972288872  931 TWVVRSYYDSKAEKCKAFWYGGCHtSSRNIWFDKETCRTSC 971
Cdd:cd22628     12 EYVVKWYYDKQANSCAQFWYGGCE-GNRNRFETEEECRKTC 51

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 43.36 E-value: 2.79e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKCEK 1662
Cdd:cd22630      1 DACSLDQDEGE-CQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALCVK 55

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 43.21 E-value: 3.00e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22604      6 CSPTADSGP-CFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 43.01 E-value: 3.08e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22596      3 CKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 43.12 E-value: 3.11e-05

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22605     17 RWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Epidermal growth factor domain, found in epidermal growth factor (EGF) presents in a large number of proteins, mostly animal; the list of proteins currently known to contain one or more copies of an EGF-like pattern is large and varied; the functional significance of EGF-like domains in what appear to be unrelated proteins is not yet clear; a common feature is that these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G/H synthase); the domain includes six cysteine residues which have been shown to be involved in disulfide bonds; the main structure is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet; Subdomains between the conserved cysteines vary in length; the region between the 5th and 6th cysteine contains two conserved glycines of which at least one is present in most EGF-like domains; a subset of these bind calcium.

Pssm-ID: 238010 Cd Length: 36 Bit Score: 42.46 E-value: 3.15e-05

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1972288872   16 ECDNGAVCGPNARCVNEIGSFQCVCDAGFSTDGDC 50
Cdd:cd00053      1 ECAASNPCSNGGTCVNTPGSYRCVCPPGYTGDRSC 35

Kunitz-type toxin huwentoxin-XI; This model contains Kunitz-type serine protease inhibitor huwentoxin-XI, including U15-theraphotoxin-Hs1g (also called U15-TRTX-Hs1g or Huwentoxin HW11c39), and kappaPI-theraphotoxin-Hs1a (also called KappaPI-TRTX-Hs1a or Huwentoxin-HW11g8). Huwentoxin-XI is a bifunctional toxin that inhibits both serine proteases (trypsin) and voltage-gated potassium channels (Kv) via surfaces displayed on opposite faces of the toxin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438641 Cd Length: 53 Bit Score: 43.06 E-value: 3.17e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNkrARQCKGFHYTGCGKSGNNFLTKEECQTKCEK 1662
Cdd:cd22598      1 DTCRLPSDRGR-CKASFERWYFN--GRTCAKFIYGGCGGNDNKFPTQEACMKRCAK 53

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438638 Cd Length: 56 Bit Score: 43.20 E-value: 3.20e-05

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1972288872 1431 FYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22595     20 FYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 42.82 E-value: 3.48e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1345 CLEPVEIGSCQETYPAFYYDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22604      6 CSPTADSGPCFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 42.80 E-value: 3.60e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1200 ACLQPFDTTyetSCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22603      2 DCLLPSETG---PCKGSFPR--YYYDKETGKCKEFIYGGCQG-NANNFETKEECERAC 53

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438675 Cd Length: 55 Bit Score: 42.80 E-value: 3.60e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1972288872 1615 RGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKCE 1661
Cdd:cd22632     10 RGP-CRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTCK 55

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 42.85 E-value: 3.85e-05

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972288872 1407 DCHLPMHIGygknedSClpQAGF-RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22621      2 FCHLPKVVG------RC--RASFpRWWYNATSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 42.74 E-value: 4.31e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22629      1 DICKLPKDEGT-CRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 42.34 E-value: 4.95e-05

                           10        20
                   ....*....|....*....|....*....
gi 1972288872 1511 NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22613     26 TRQCEEFIYGGCEGNENRFETLEECKKTC 54

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 42.34 E-value: 5.03e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1485 CFEPPgDRGICGKNSSTnplkrWTYGNQK--CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22637      1 CDQPK-DTGPCDNWVLK-----WYYDSKKgsCRQFYYGGCGGNDNRFDTEEECEARC 51

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 42.25 E-value: 5.21e-05

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 1972288872   668 DLCDEPLHPKleeDCKNdqWEIQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:smart00131    1 DVCLLPPDTG---PCGG--SIPRYYYDPETGTCEPFTYGGCG-GNANNFESLEECERTC 53

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 42.35 E-value: 5.24e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1972288872  680 EDCKNDQweIQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd22605      9 EDCGEEQ--VRWYFDAKRGNCFTFTYGGCD-GNRNHFETYEECRLAC 52

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 42.18 E-value: 5.96e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22639      1 CSLPKDRGP-CRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 42.03 E-value: 5.98e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22607      2 CSEQAETGP-CRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 42.14 E-value: 6.33e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1972288872 1408 CHLPMHIGYGKnedsclpqAGF-RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22618      2 CSEPKVVGPCK--------AYFpRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 42.14 E-value: 7.01e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1201 CLQPFDTTYetsCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22633      5 CLLPKDVGG---CRARFPR--YYYNSSTRRCEKFRYGGCGG-NANNFHTLEECEKVC 55

Kunitz protease inhibitor (KPI) domain 1 (KPI-1 or K1) of tissue factor pathway inhibitor (TFPI); This model represents the first Kunitz-type domain (K1 or KPI-1) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; The K1 domain of TFPI has been shown to bind and inhibit FVIIa while the K2 domain similarly inhibits FXa. Small peptide blocking inhibition of FXa and TF-FVIIa by TFPI shows that domain K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. The structure of the K1 domain is similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438656 Cd Length: 55 Bit Score: 41.96 E-value: 7.06e-05

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1222 YYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22613     20 FFFNIFTRQCEEFIYGGCEG-NENRFETLEECKKTC 54

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 42.08 E-value: 7.52e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1213 CSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22599     15 CRALIPR--FYFNTETGQCTEFIYGGCGG-NENNFETIEECEKAC 56

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 41.96 E-value: 7.75e-05

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1972288872 1432 YYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22637     18 YYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 41.96 E-value: 8.16e-05

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22605      2 CLKEPDRED-CGEEQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 42.01 E-value: 9.18e-05

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1408 CHLPMHIGYgknedsCLpqAGF-RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCSQS 1468
Cdd:cd22611      3 CSLPKESGP------CM--AYFpRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNICKKK 56

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 41.44 E-value: 9.43e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1972288872  681 DCKNdqWEIQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd22631      9 SCQN--YTMMWFFDSKQGRCSRFWYGGCG-GNANRFETQEECENLC 51

Kunitz-type domain from the alpha1 chain of type XXVIII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type XXVIII collagen (collagen alpha-1(XXVIII) chain) and similar proteins. The zebrafish has four collagen XXVIII genes all of which are differentially expressed in the liver, thymus, muscle, intestine and skin; only the alpha1 chain contains the Kunitz domain which is often proteolytically processed. Mammals only contain the alpha1 collagen chain, expressed mostly in dorsal root ganglia and peripheral nerves. The Kunitz domain is found at the C-terminus, and is most related to Kunitz domains of papilin and alpha3(VI) collagen. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438671 Cd Length: 51 Bit Score: 41.50 E-value: 1.05e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872  670 CDEPLHPKleeDCKNdqWEIQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd22628      1 CLEPLDPG---PCRE--YVVKWYYDKQANSCAQFWYGGCE-GNRNRFETEEECRKTC 51

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 41.28 E-value: 1.12e-04

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22609     17 RYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 41.48 E-value: 1.13e-04

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|..
gi 1972288872    73 GKQEIKYYYDADSVQCKQFFYGGCKtTSRNFFADLQTCDVIC 114
Cdd:smart00131   13 GGSIPRYYYDPETGTCEPFTYGGCG-GNANNFESLEECERTC 53

EGF domain; This family includes a variety of EGF-like domain homologs. This family includes the C-terminal domain of the malaria parasite MSP1 protein.

Pssm-ID: 463759 [Multi-domain] Cd Length: 36 Bit Score: 40.66 E-value: 1.45e-04

                           10        20
                   ....*....|....*....|....*.
gi 1972288872   23 CGPNARCVNEIGSFQCVCDAGFSTDG 48
Cdd:pfam12947    8 CHPNATCTNTGGSFTCTCNDGYTGDG 33

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 41.06 E-value: 1.48e-04

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1221 YYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22631     16 MWFFDSKQGRCSRFWYGGCGG-NANRFETQEECENLC 51

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 41.07 E-value: 1.62e-04

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1198 TQACLQPFDttyETSCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWICER 1259
Cdd:cd22616      2 AEICLLPPD---EGPCRALIPR--YYYDRYTQTCREFSYGGCEG-NANNFESLEDCEKTCWR 57

Stichodactyla helianthus Kunitz inhibitor protein ShPI-1, Heteractis crispa protease inhibitor stichotoxin-Hcr2e, and similar proteins; This model includes Kunitz inhibitor protein ShPI-1, the major protease inhibitor from the sea anemone Stichodactyla helianthus, as well as protease inhibitor stichotoxin-Hcr2e (also called PI- stichotoxin-Hcr2e, PI-SHTX-Hcr2e, or Kunitz-type serine protease inhibitor InhVJ) and HCRG1 from Heteractis crispa. ShPI-1 has an unusually broad specificity toward several serine proteases, including trypsin, chymotrypsin, human neutrophil elastase, kallikrein and plasmin, and can also bind aspartic and cysteine proteases, such as pepsin and papain, respectively. PI-SHTX-Hcr2e and HCRG1 inhibit trypsin and chymotrypsin, but do not inhibit the serine proteases plasmin, thrombin, kallikrein, the cysteine proteinase papain, and the aspartic protease pepsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438661 Cd Length: 53 Bit Score: 40.98 E-value: 1.87e-04

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22618     11 CKAYFPRFYFDSETGKCTPFIYGGCGGNGNNFETLHACRAIC 52

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438650 Cd Length: 52 Bit Score: 40.87 E-value: 1.87e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1494 ICGKNSSTNP----LKRWTY--GNQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22607      1 VCSEQAETGPcramMPRWYFdvTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Kunitz domain of epididymal protease inhibitor eppin and similar proteins; This subfamily includes the Kunitz inhibitor domain protein eppin (also called Cancer/testis antigen 71 or CT71, epididymal protease inhibitor, protease inhibitor WAP7, serine protease inhibitor-like with Kunitz and WAP domains 1, or WAP four-disulfide core domain protein 7) as well as WAP four-disulfide core domain proteins 6A and 6B in mice, and similar proteins. Eppin is a serine protease inhibitor that plays an essential role in male reproduction and fertility. It modulates the hydrolysis of seminal fluid protein semenogelin 1 (SEMG1) by the serine protease kallikrein-related peptidase 3 (KLK3, PSA), provides antimicrobial protection for spermatozoa in the ejaculate coagulum, and binds SEMG1, thereby inhibiting sperm motility. Thus, eppin could potentially be used as a target for male contraception. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438654 Cd Length: 57 Bit Score: 40.85 E-value: 2.06e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1607 DPCMESLDRGSwCEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKCEKR 1663
Cdd:cd22611      1 DVCSLPKESGP-CMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNICKKK 56

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 40.61 E-value: 2.19e-04

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872  691 WFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd00109     17 WYYNSETGQCEEFIYGGCG-GNANNFETKEECEATC 51

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 40.92 E-value: 2.42e-04

                           10        20
                   ....*....|....*....|....*....
gi 1972288872 1513 KCTSFTYSGCGGNRNRFATQDICENTCNG 1541
Cdd:cd22599     30 QCTEFIYGGCGGNENNFETIEECEKACGA 58

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 40.76 E-value: 2.50e-04

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1222 YYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWICE 1258
Cdd:cd22614     21 YFYNNQSKQCERFKYGGCLG-NQNNFESLEECQNTCE 56

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 40.51 E-value: 2.61e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1972288872 1420 EDSCLPQA------GF--RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22604      3 EKQCSPTAdsgpcfAYfpMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 56

Kunitz-type serine protease inhibitor 6 (BmTI-6), A (BmTI-A), and similar proteins; This group includes Kunitz-type serine protease inhibitors 6 (BmTI-6) and A (BmTI-A), both of which inhibit bovine trypsin, bovine chymotrypsin, human plasmin, human plasma kallikrein and human neutrophil elastase, but not bovine thrombin, human factor Xa or porcine pancreatic kallikrein. They may play a role in blocking blood coagulation during the larvae fixation on cattle. This subfamily also includes Rhipicephalus microplus protease inhibitor carrapatin. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438647 [Multi-domain] Cd Length: 56 Bit Score: 40.13 E-value: 3.21e-04

                           10        20
                   ....*....|....*....|....*..
gi 1972288872 1513 KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22604     30 QCEEFIYGGCQGNDNRYETEEECEKTC 56

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 39.93 E-value: 3.47e-04

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872  689 IQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd22592     16 IRYFYNAKSGLCETFVYGGCR-AKRNNFLSAEDCMRTC 52

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 39.94 E-value: 3.67e-04

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1972288872 1076 PCGDgksWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:cd22635     10 VCGD---YVQRWYYDPATGACNRFWYGGC-GGNANRFATEAECLRTC 52

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438678 Cd Length: 52 Bit Score: 39.94 E-value: 3.75e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1269 CADKFDTkyTESCGDsqWTEKWYFDQSSGDCSSFWWDECTSSSqNIFPDEKSCTSNC 1325
Cdd:cd22635      1 CLLDKDA--GTVCGD--YVQRWYYDPATGACNRFWYGGCGGNA-NRFATEAECLRTC 52

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 39.55 E-value: 4.58e-04

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|..
gi 1972288872  1149 GEFTNRFYFDHDRKKCVAFHWGGCQSkSQNFFADMTVCQDLC 1190
Cdd:smart00131   13 GGSIPRYYYDPETGTCEPFTYGGCGG-NANNFESLEECERTC 53

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 39.65 E-value: 5.02e-04

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1284 SQWTEKWYFDQSSGDCSSFWWDECTSSSqNIFPDEKSCTSNC 1325
Cdd:cd22637     11 DNWVLKWYYDSKKGSCRQFYYGGCGGND-NRFDTEEECEARC 51

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 39.59 E-value: 5.11e-04

                           10        20
                   ....*....|....*....|....*.
gi 1972288872   78 KYYYDADSVQCKQFFYGGCKTTSRNF 103
Cdd:cd22608     19 RFYYNSASNKCQQFIYGGCKGNANNF 44

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 39.65 E-value: 5.33e-04

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22622     18 RWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 39.26 E-value: 5.99e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872  915 CDDEYDPKwdeDClgDTWVVRSYYDSKAEKCKAFWYGGCHTSSrNIWFDKETCRTSC 971
Cdd:cd22637      1 CDQPKDTG---PC--DNWVLKWYYDSKKGSCRQFYYGGCGGND-NRFDTEEECEARC 51

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 39.16 E-value: 6.98e-04

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22592     17 RYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 52

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 38.98 E-value: 7.95e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGYGKnedSCLPqagfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22626      1 CSLELDYGVGK---AYIP----RWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

Kunitz-type domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. It has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer, the loss of which leads to tumor growth and progression attributable at least in part to increased MET signaling. HAI-2 is a specific substrate of mesotrypsin which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in hetatocyte growth factor/scatter factor (HGF/SF) activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. KD2 is similar to KD1, whose structure is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438665 Cd Length: 53 Bit Score: 38.88 E-value: 8.06e-04

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1506 RWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22622     18 RWYYDpeSQSCKEFIYGGCRGNKNNYLSEEECMDRC 53

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 38.88 E-value: 8.64e-04

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGYGKNEDSclpqagfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22606      2 CSLPAVQGPCKAWEP-------RWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 39.06 E-value: 9.50e-04

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1506 RWTYGNQ--KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22633     20 RYYYNSStrRCEKFRYGGCGGNANNFHTLEECEKVC 55

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 38.76 E-value: 1.03e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1086 RYFYDKDTRSCRMFWSNGCFSSSkNNFDDLETCQWKC 1122
Cdd:cd22616     20 RYYYDRYTQTCREFSYGGCEGNA-NNFESLEDCEKTC 55

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 38.78 E-value: 1.07e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1149 GEFTNRFYFDHDRKKCVAFHWGGCQSKsQNFFADMTVCQDLC 1190
Cdd:pfam00014   12 KASIPRWYYNPTTGTCEPFTYGGCGGN-ANNFESLEECESTC 52

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 38.68 E-value: 1.08e-03

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1972288872  937 YYDSKAEKCKAFWYGGCHtSSRNIWFDKETCRTSC 971
Cdd:cd00109     18 YYNSETGQCEEFIYGGCG-GNANNFETKEECEATC 51

Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6), Amblyomma hebraeum amblin domain 1, and similar proteins; This model includes Caenorhabditis elegans Kunitz domain 11 of papilin (also called abnormal cell migration protein 6 or mig-6) and domain 1 of Amblyomma hebraeum amblin, and similar proteins. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. Amblin contains two Kunitz-like domains and specifically inhibits thrombin. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438680 Cd Length: 51 Bit Score: 38.52 E-value: 1.11e-03

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1222 YYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22638     17 WYYDPSTQSCKTFIYGGCGG-NGNRFDSEEDCQETC 51

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 38.30 E-value: 1.45e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1146 CRhgEFTNRFYFDHDRKKCVAFHWGGCQsKSQNFFADMTVCQDLC 1190
Cdd:cd00109     10 CR--AYFPRWYYNSETGQCEEFIYGGCG-GNANNFETKEECEATC 51

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 38.29 E-value: 1.47e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22602     10 CRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 38.12 E-value: 1.59e-03

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1222 YYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22629     19 WYYDPETKSCARFWYGGCGG-NENRFDSQEECEKVC 53

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 38.35 E-value: 1.61e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1221 YYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22630     18 KWYYDQEQKECSQFWYGGCGG-NKNRFETQEECEALC 53

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 38.01 E-value: 1.75e-03

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|
gi 1972288872   932 WVVRSYYDSKAEKCKAFWYGGCHtSSRNIWFDKETCRTSC 971
Cdd:smart00131   15 SIPRYYYDPETGTCEPFTYGGCG-GNANNFESLEECERTC 53

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438677 Cd Length: 57 Bit Score: 38.26 E-value: 1.75e-03

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972288872 1408 CHLPMHIGYGkNEDSClpqAGF--RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22634      2 CGQPHSLGGG-DGISC---FAYipSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 38.01 E-value: 1.76e-03

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 1972288872  933 VVRSYYDSKAEKCKAFWYGGCHTsSRNIWFDKETCRTSC 971
Cdd:pfam00014   15 IPRWYYNPTTGTCEPFTYGGCGG-NANNFESLEECESTC 52

Kunitz-type domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2), and similar proteins; This model includes the Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 2 (HAI-2 or HAI2, also known as placental bikunin or Kunitz-type protease inhibitor 2). HAI-2 is composed of two Kunitz domains that strongly inhibit many serine proteases with sub-nanomolar affinities. HAI-2 Kunitz domain 1 (KD1) has been found to be the domain responsible for inhibition of hepatocyte growth factor (HGF) activator; activated HGF/scatter factor (HGF/SF) binds to its receptor tyrosine kinase MET to induce dimerization and initiate phosphorylation cascades leading to comprehensive cellular changes that, in the deregulated context of cancer, drive malignant transformation and progression. HAI-2 has been found to be a natural tumor suppressor in renal cell carcinoma, breast cancer and prostate cancer; its loss leads to tumor growth and progression in part due to increased MET signaling. HAI-2 is also a specific substrate for mesotrypsin, which is up-regulated with progression in prostate cancers and shown to contribute to invasion and metastasis; these activities of mesotrypsin may in part be mediated through cleavage and inactivation of HAI-2, resulting in increases in HGF/SF activation and MET signaling. HAI-2 is a physiological inhibitor of hepsin and matriptase, two type II transmembrane serine proteases that, like HGF activator, can convert latent pro-HGF/SF into the two-chain active signaling heterodimer. The structures of these KD1 domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438664 Cd Length: 53 Bit Score: 38.22 E-value: 1.77e-03

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1506 RWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22621     18 RWWYNatSQSCQEFIFGGCKGNLNNFLSEQECLQKC 53

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 38.06 E-value: 1.83e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1491 DRGICgknssTNPLKRWTYGNQ--KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22614     10 DPGIC-----RGLITRYFYNNQskQCERFKYGGCLGNQNNFESLEECQNTC 55

Tick anticoagulant peptide, and similar proteins; Tick anticoagulant peptide (TAP) is a competitive inhibitor of factor Xa, a serine protease that converts prothrombin into thrombin, which acts to convert fibrinogen into fibrin, the insoluble matrix of blood clots. TAP is one of the antihemostatic components evolved in the blood-feeding tick. This subfamily also includes the N-terminal Kunitz inhibitor domain of ornithodorin which binds to the active site of thrombin, while the C-terminal domain binds at the fibrinogen recognition exosite. The TAP structure is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438634 Cd Length: 60 Bit Score: 38.32 E-value: 1.91e-03

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1972288872  912 NDPCDDEYDPKWDEDCLGDTWVVRSYYDSKAEkCKAFWYGGCHTSSRNIWFDKETCRTSC 971
Cdd:cd21630      1 NRLCDKPRGPDLTEECDSEAWERRYFRNGKGG-CESFWYCDEEDTGANYFSSMEDCFNAC 59

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438666 Cd Length: 59 Bit Score: 38.29 E-value: 1.91e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1430 RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTCS 1466
Cdd:cd22623     21 RWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSACR 57

Epidermal growth factor-like domain;

Pssm-ID: 214544 Cd Length: 35 Bit Score: 37.50 E-value: 1.96e-03

                            10        20        30
                    ....*....|....*....|....*....|....*.
gi 1972288872    16 ECDNGAVCGpNARCVNEIGSFQCVCDAGFSTDGDCK 51
Cdd:smart00181    1 ECASGGPCS-NGTCINTPGSYTCSCPPGYTGDKRCE 35

Kunitz protease inhibitor (KPI) domain 2 (KPI-2 or K2) of tissue factor pathway inhibitor (TFPI); This model represents the second Kunitz-type domain (K2 or KPI-2) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI). TFPI down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI complex that then slowly isomerizes to a tight FXa-TFPI* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; the K2 domain is exposed on functionally active TFPI pools in circulation in blood, in platelets, and attached to the endothelium. While the K1 (or KPI-1) domain of TFPI has been shown to bind and inhibit FVIIa, the K2 domain inhibits FXa by binding directly to the active site and forming a FXa:TFPI complex. A close interaction between the TFPI K2 domain and the FXa active site is essential for the FXa inhibitory action of TFPI and for the formation of an inactive TF/FVIIa/FXa/TFPI complex which then prevents FXa generation. Thus, blockage of K2 would prevent TFPI binding to both FXa and FVIIa/TF, and fully abolish TFPI inhibition of the coagulation cascade. The structure of the K2 domain is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438657 Cd Length: 56 Bit Score: 38.06 E-value: 2.03e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872  242 KFFWNSEFKDCEPFWYdSSCdprdRAGKNFFETFEDCKNKCD 283
Cdd:cd22614     20 RYFYNNQSKQCERFKY-GGC----LGNQNNFESLEECQNTCE 56

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 37.82 E-value: 2.09e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1609 CMESLDRGSWcEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22626      1 CSLELDYGVG-KAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 51

Kunitz domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 2 (KD2) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438660 Cd Length: 54 Bit Score: 37.75 E-value: 2.13e-03

                           10        20
                   ....*....|....*....|....*...
gi 1972288872 1512 QKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22617     27 MRCEEFTYGGCYGNGNNFRDKSSCISAC 54

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438681 Cd Length: 52 Bit Score: 37.94 E-value: 2.16e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1972288872 1280 SCGDsqWTEKWYFDQSSGDCSSFWWDECtSSSQNIFPDEKSCTSNC 1325
Cdd:cd22639      9 PCRN--YTVKWYFDMAYGGCSRFWYGGC-GGNGNRFDTEEECKAVC 51

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

Pssm-ID: 438636 Cd Length: 51 Bit Score: 37.59 E-value: 2.16e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1078 GDGKSWSNRYFYDKDTRSCRMFWSNGcFSSSKNNFDDLETCQWKC 1122
Cdd:cd22593      8 GSGNSSLTRWYYDPKKGQCKPFTYKG-KGGNENNFLTKEDCEETC 51

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 37.81 E-value: 2.22e-03

                           10        20
                   ....*....|....*....|....*.
gi 1972288872 1514 CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22609     27 CEQFVYGGCGGNRNNFLTLEDCMKTC 52

first Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438642 Cd Length: 61 Bit Score: 37.84 E-value: 2.33e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1154 RFYFDHDRKKCVAFHWGGCQSKSQNFFAdMTVCQDLCESPPR 1195
Cdd:cd22599     21 RFYFNTETGQCTEFIYGGCGGNENNFET-IEECEKACGAPER 61

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

Pssm-ID: 197529 Cd Length: 53 Bit Score: 37.63 E-value: 2.35e-03

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872  1268 ICADKFDTKYtesCGdsQWTEKWYFDQSSGDCSSFWWDECtSSSQNIFPDEKSCTSNC 1325
Cdd:smart00131    2 VCLLPPDTGP---CG--GSIPRYYYDPETGTCEPFTYGGC-GGNANNFESLEECERTC 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 37.62 E-value: 2.50e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872  674 LHPKLEEDCKndQWEIQWFFNSDRGACKSFWYGGCEIESRNFFpDHANCRHSC 726
Cdd:pfam00014    3 SLPPDSGPCK--ASIPRWYYNPTTGTCEPFTYGGCGGNANNFE-SLEECESTC 52

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438659 Cd Length: 57 Bit Score: 37.60 E-value: 2.52e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872   78 KYYYDADSVQCKQFFYGGCKTTSRNfFADLQTCDVIC 114
Cdd:cd22616     20 RYYYDRYTQTCREFSYGGCEGNANN-FESLEDCEKTC 55

Kunitz/Bovine pancreatic trypsin inhibitor (BPTI) domain; This family contains the Kunitz domain which is a common structural fold found in a family of reversible serine protease inhibitors. This domain is thought to have evolved over 500 million years and is ubiquitous in all kingdoms of life and has been incorporated into many different genes. In general, each domain is encoded by a single exon. Some genes encode proteins with a single Kunitz domain, e.g. bovine pancreatic trypsin inhibitor (BPTI), trophoblast Kunitz domain protein (TKDP), amyloid beta-protein precursor (ABPP), as well as Kunitz-type venom peptides such as dendrotoxin. Genes that encode multiple Kunitz domains include hepatocyte growth factor activator inhibitors HAI1 and HAI2 (two domains), tissue factor pathway inhibitor TFPI1 and TFPI2 (three domains) and Caenorhabditis elegans papilin (eleven domains). In addition, the Kunitz domain has been integrated into multi-domain proteins, e.g. the collagen alpha3(VI), alpha1(VII) and alpha1(XXVIII) chains, WFIKKN1 (containing WAP, Follistatin/Kazal, Immunoglobulin, two Kunitz and NTR domains) and papilin. Furthermore, each domain within a multi-Kunitz domain protein may exhibit different protease activity, such as for the three tandemly repeated domains within both tissue factor pathway inhibitors 1 and 2. The Kunitz domain is a representative of alpha/beta proteins with irregular secondary structure stabilized by three disulfide bonds and presenting three peptide loops that can be varied without introducing much destabilization to the scaffold. Protease inhibitors meet the scaffold criteria in that they are small, stable and capable of evolving the binding activity of exposed peptide loops through targeted randomization to construct combinatorial libraries. Kunitz domain-based scaffolds have been successfully utilized to construct and select a library of protease inhibitors with the potential for therapeutic application.

Pssm-ID: 438633 Cd Length: 51 Bit Score: 37.53 E-value: 2.75e-03

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 1972288872   76 EIKYYYDADSVQCKQFFYGGCKtTSRNFFADLQTCDVIC 114
Cdd:cd00109     14 FPRWYYNSETGQCEEFIYGGCG-GNANNFETKEECEATC 51

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438645 Cd Length: 51 Bit Score: 37.52 E-value: 2.84e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGygknedSCLPQAGfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22602      1 CSLPSKVG------PCRVSAR-RWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Pseudocerastes persicus trypsin inhibitor (PPTI), Kunitz-type serine protease inhibitor bitisilin, and similar proteins; This group contains Pseudocerastes persicus trypsin inhibitor (PPTI), Bitis gabonica Kunitz-type serine protease inhibitor bitisilin-1 (BG-11), -2 (BG-15) and -3 (two-Kunitz protease inhibitor), Oxyuranus scutellatus scutellatus taicatoxin, and serine protease inhibitor component (TSPI, also called venom protease inhibitor 1 or venom protease inhibitor 2), among others. PPTI from P. persicus venom shows inhibitory effect against trypsin proteolytic activity and has similarities to dendrotoxins (DTXs), with corresponding functionally important residues. Studies have shown the ability of PPTI to inhibit voltage-gated potassium channels, and consequently have dual functionality. Bitilisins 1, 2, and 3 are serine protease inhibitors expressed in snake venom glands; bitsilin-3 consists of two Kunitz protease inhibitor domains. Taicatoxin inhibits trypsin, tissue kallikrein, elastase, plasmin and factor Xa, and is also known to block the voltage-dependent L-type calcium channels from the heart, and the small conductance calcium-activated potassium channels (KCa) in chromaffin cells and in the brain. The structures of these Kunitz-type proteins are similar to other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438651 Cd Length: 54 Bit Score: 37.66 E-value: 2.98e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872  935 RSYYDSKAEKCKAFWYGGCHTSSRNiWFDKETCRTSC 971
Cdd:cd22608     19 RFYYNSASNKCQQFIYGGCKGNANN-FETKDECRYTC 54

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 37.41 E-value: 3.04e-03

                           10        20
                   ....*....|....*....|....*.
gi 1972288872   78 KYYYDADSVQCKQFFYGGCKTTSRNF 103
Cdd:cd22603     18 RYYYDKETGKCKEFIYGGCQGNANNF 43

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 37.34 E-value: 3.36e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1078 GDGKSWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:cd22637      8 GPCDNWVLKWYYDSKKGSCRQFYYGGC-GGNDNRFDTEEECEARC 51

Kunitz-type serine protease inhibitor subunit of beta 2-bungarotoxin, and similar proteins; This model includes the Kunitz inhibitor subunit of beta 2-bungarotoxin, a presynaptic neurotoxin of the Bungarus multicinctus venom. Beta-bungarotoxin is a heterodimeric neurotoxin consisting of a phospholipase subunit linked by a disulfide bond to the Kunitz protease inhibitor subunit; the latter subunit is homologous to venom basic protease inhibitors but has no protease inhibitor activity and is non-toxic. The beta-bungarotoxin Kunitz subunit serves to guide the toxin to its site of action on the presynaptic membrane by virtue of a high-affinity interaction with a specific subclass of voltage-sensitive potassium channels. This subfamily also includes Kunitz-type serine protease inhibitor homolog beta-bungarotoxin B1 chain and protease inhibitor-like protein 1 (PILP-1). The B1 chain also has no protease inhibitor activity but blocks voltage-gated potassium channels, while PILP-1 inhibits trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438662 Cd Length: 58 Bit Score: 37.54 E-value: 3.42e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1972288872 1619 CEAMSNRYYFNKRARQCKGFHYTGCGKSGNNFLTKEECQTKC 1660
Cdd:cd22619     16 CKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438672 Cd Length: 53 Bit Score: 36.96 E-value: 3.98e-03

                           10        20
                   ....*....|....*....|....
gi 1972288872  930 DTWVVRSYYDSKAEKCKAFWYGGC 953
Cdd:cd22629     13 RDFVLKWYYDPETKSCARFWYGGC 36

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 36.85 E-value: 4.30e-03

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872   76 EIKYYYDADSVQCKQFFYGGCKTTSRNFFAD---LQTC 110
Cdd:cd22596     16 IQRYFYNSSSMACQTFNYGGCLGNQNNFVTEkecLQTC 53

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 37.20 E-value: 4.34e-03

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1972288872  676 PKLEEDCKNdqWEIQWFFNSDRGACKSFWYGGCE 709
Cdd:cd22630      6 DQDEGECQN--YVLKWYYDQEQKECSQFWYGGCG 37

Tick anticoagulant peptide, and similar proteins; Tick anticoagulant peptide (TAP) is a competitive inhibitor of factor Xa, a serine protease that converts prothrombin into thrombin, which acts to convert fibrinogen into fibrin, the insoluble matrix of blood clots. TAP is one of the antihemostatic components evolved in the blood-feeding tick. This subfamily also includes the N-terminal Kunitz inhibitor domain of ornithodorin which binds to the active site of thrombin, while the C-terminal domain binds at the fibrinogen recognition exosite. The TAP structure is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438634 Cd Length: 60 Bit Score: 37.16 E-value: 4.41e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1972288872 1267 AICADKFDTKYTESCGDSQWTEKWYFDqSSGDCSSFWWDECTSSSQNIFPDEKSCTSNC 1325
Cdd:cd21630      2 RLCDKPRGPDLTEECDSEAWERRYFRN-GKGGCESFWYCDEEDTGANYFSSMEDCFNAC 59

Kunitz protease inhibitor (KPI) domain 3 (KPI-3 or K3) of tissue factor pathway inhibitor (TFPI) and TFPI2, and similar proteins; This model represents the third Kunitz-type domain (K3 or KPI-3) of tissue factor pathway inhibitor (TFPI or TFPI1), also known as extrinsic pathway inhibitor (EPI) or lipoprotein-associated coagulation inhibitor (LACI), and of TFPI2 (or TFPI-2). TFPI1 down-regulates the extrinsic coagulation pathway via inhibition of activated factor X (FXa or Xa) and FVIIa (VIIa). It inhibits activated FXa via a "slow-tight binding mechanism", i.e. rapid formation of a loose FXa-TFPI1 complex that then slowly isomerizes to a tight FXa-TFPI1* complex. Subsequent inhibition of FVIIa is facilitated by the presence of tissue factor (TF) and FXa, which together rapidly and efficiently form a quaternary FXa-TFPI1-TF-FVIIa complex in which the activity of FXa and FVIIa are inhibited. TFPI1 consists of 3 Kunitz-type protease inhibitor (KPI) domains in a tandem arrangement; while the K1 domain of TFPI has been shown to bind and inhibit FVIIa and the K2 domain similarly inhibits FXa, the K3 domain has no known inhibitory function. However, Protein S, which functions as a cofactor for TFPI to efficiently enhance TFPI inhibition of FXa and FXa activated TF-VIIa, is dependent on direct interactions with two important residues within K3, a Glutamate and an Arginine. This model also includes TFPI2 Kunitz domain 3 (KD3). TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. While TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1, domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438658 Cd Length: 54 Bit Score: 36.89 E-value: 4.44e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1972288872 1201 CLQPFDttyETSCSAEKPQqyYYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22615      4 CLSPKD---EGLCSASVTR--YYYNSATKTCEPFNYTGCGG-NNNNFTSKKDCLRVC 54

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438648 Cd Length: 52 Bit Score: 36.95 E-value: 4.62e-03

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872  934 VRSYYDSKAEKCKAFWYGGCHtSSRNIWFDKETCRTSC 971
Cdd:cd22605     16 VRWYFDAKRGNCFTFTYGGCD-GNRNHFETYEECRLAC 52

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 36.98 E-value: 5.00e-03

                           10        20
                   ....*....|....*....|....*..
gi 1972288872 1513 KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22597     28 KCVPFSYGGCQGNGNKFYSEKECEEYC 54

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 36.47 E-value: 5.64e-03

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1972288872 1485 CFEPPgdrgicgknsSTNPLK----RWTYgNQK---CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22592      2 CLEPP----------YTGPCKariiRYFY-NAKsglCETFVYGGCRAKRNNFLSAEDCMRTC 52

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438679 Cd Length: 51 Bit Score: 36.56 E-value: 6.01e-03

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1972288872 1222 YYFDMSSGICKMFWFGNCKGeNQNIFSTLEACQWIC 1257
Cdd:cd22637     17 WYYDSKKGSCRQFYYGGCGG-NDNRFDTEEECEARC 51

Kunitz-type domain 1 (K1) of Ixolaris, and similar proteins; This model includes the first Kunitz-type domain (K1) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. While K2 is an extraordinarily dynamic domain that encompasses several residues involved in FX binding, K1 domain keeps as a rigid platform supporting the conformational dynamic of the K2 domain, forming a salt bridge with FXa. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438668 Cd Length: 53 Bit Score: 36.47 E-value: 6.17e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMhigygKNEDSCLPQAGFRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22625      1 CTLPI-----QEITTCESQPTKRYGYNKKTQQCEEFLGTECGGGGNSFEEAKECWSSC 53

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 36.74 E-value: 6.36e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872   78 KYYYDADSVQCKQFFYGGCKTTSRNFFAdLQTCDVIC 114
Cdd:cd22633     20 RYYYNSSTRRCEKFRYGGCGGNANNFHT-LEECEKVC 55

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

Pssm-ID: 438640 Cd Length: 55 Bit Score: 36.59 E-value: 6.52e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1972288872 1408 CHLPMHIGygknedSCLPQAGfRFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22597      4 CRLPIVPG------PCKGFVD-LWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYC 54

Kunitz-type domain 2 (K2) of Ixolaris, and similar proteins; This model includes the second Kunitz-type domain (K2) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. This model contains K2, an extraordinarily dynamic domain that encompasses several residues involved in FX binding. Its backbone plasticity is critical for ixolaris biological activity. This domain contains 2 disulfide bonds instead of the 3 typical of Kunitz domain proteins.

Pssm-ID: 438669 Cd Length: 51 Bit Score: 36.28 E-value: 6.61e-03

                           10        20        30
                   ....*....|....*....|....*....|....*...
gi 1972288872 1504 LKRWTYG--NQKCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22626     14 IPRWYFNtsNARCEMFIFGGIGGNKNNFETLEECKKTC 51

Kunitz-type domain 1 (K1) of Ixolaris, and similar proteins; This model includes the first Kunitz-type domain (K1) of ixolaris from the venomous organism Conus striatus. Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, and forms a quaternary tissue factor (TF)/FVIIa/FX(a)/Ixolaris inhibitory complex. It blocks TF-induced coagulation and PAR2 (proteinase-activated receptor 2) signaling, and prevents thrombosis, tumor growth, and immune activation. Ixolaris consists of 2 Kunitz domains (K1 and K2), both of which recognize the heparin-binding (pro)exosite (HBE) on FX. While K2 is an extraordinarily dynamic domain that encompasses several residues involved in FX binding, K1 domain keeps as a rigid platform supporting the conformational dynamic of the K2 domain, forming a salt bridge with FXa. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438668 Cd Length: 53 Bit Score: 36.47 E-value: 6.75e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872 1345 CLEPV-EIGSCQETYPAFY-YDRASRTCRPFAYSGCGGNSNRFMTVSQCENLC 1395
Cdd:cd22625      1 CTLPIqEITTCESQPTKRYgYNKKTQQCEEFLGTECGGGGNSFEEAKECWSSC 53

Kunitz-type domain from the alpha6 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain), encoded by COL6A6 gene, and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438673 Cd Length: 55 Bit Score: 36.43 E-value: 6.97e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1972288872   76 EIKYYYDADSVQCKQFFYGGCKtTSRNFFADLQTCDVICVS 116
Cdd:cd22630     16 VLKWYYDQEQKECSQFWYGGCG-GNKNRFETQEECEALCVK 55

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438646 Cd Length: 53 Bit Score: 36.25 E-value: 7.24e-03

                           10        20
                   ....*....|....*....|....*..
gi 1972288872 1513 KCTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22603     27 KCKEFIYGGCQGNANNFETKEECERAC 53

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 36.46 E-value: 7.32e-03

                           10        20
                   ....*....|....*....|....*.
gi 1972288872 1514 CTSFTYSGCGGNRNRFATQDICENTC 1539
Cdd:cd22596     28 CQTFNYGGCLGNQNNFVTEKECLQTC 53

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 36.27 E-value: 7.62e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1972288872 1078 GDGKSWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:cd22609      9 GVCKASMTRYFYNAQTGHCEQFVYGGC-GGNRNNFLTLEDCMKTC 52

Kunitz-type domain from the alpha6 chain of fish type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha6 chain of type VI collagen (collagen alpha 6(VI) chain) and similar proteins. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438674 [Multi-domain] Cd Length: 51 Bit Score: 36.05 E-value: 7.76e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1072 SLSKPCGDGKSWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:cd22631      2 LLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGC-GGNANRFETQEECENLC 51

first Kunitz domain of bikunin and similar proteins; This subfamily includes the N-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. It is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the first repeat.

Pssm-ID: 438639 Cd Length: 54 Bit Score: 36.08 E-value: 8.24e-03

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1972288872 1407 DCHLPMHIGygknedsclPQAGF--RFYYDRNYGKCSQMWYLGCGGNANNFYSYEICQRTC 1465
Cdd:cd22596      2 SCKLPPDAG---------PCFGMiqRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

Kunitz/Bovine pancreatic trypsin inhibitor domain; Indicative of a protease inhibitor, usually a serine protease inhibitor. Structure is a disulfide rich alpha+beta fold. BPTI (bovine pancreatic trypsin inhibitor) is an extensively studied model structure. Certain family members are similar to the tick anticoagulant peptide (TAP). This is a highly selective inhibitor of factor Xa in the blood coagulation pathways. TAP molecules are highly dipolar, and are arranged to form a twisted two- stranded antiparallel beta-sheet followed by an alpha helix.

Pssm-ID: 425421 Cd Length: 53 Bit Score: 36.08 E-value: 8.41e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1972288872 1280 SCGDSqwTEKWYFDQSSGDCSSFWWDECtSSSQNIFPDEKSCTSNCK 1326
Cdd:pfam00014   10 PCKAS--IPRWYYNPTTGTCEPFTYGGC-GGNANNFESLEECESTCR 53

trophoblast Kunitz domain protein (TKDP) and similar proteins; This model contains the trophoblast Kunitz domain protein 1 (TKDP-1) and splice variant TKDP-4, among others, which are Kunitz inhibitor domain proteins. TKDP-1 is expressed in the trophectoderm which forms the outer epithelial layer of the trophoblast, and may play a role in mediating maternal-conceptus interactions in the immediate preimplantation period. However, it does not appear to have proteinase inhibitory activity. These domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438652 Cd Length: 52 Bit Score: 36.27 E-value: 8.50e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1972288872  674 LHPKLEEDCKnDQWeIQWFFNSDRGACKSFWYGGCEiESRNFFPDHANCRHSC 726
Cdd:cd22609      3 LEPKVVGVCK-ASM-TRYFYNAQTGHCEQFVYGGCG-GNRNNFLTLEDCMKTC 52

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

Pssm-ID: 438663 Cd Length: 58 Bit Score: 36.39 E-value: 8.67e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1972288872  929 GDTWVVRSYYDSKAEKCKAFWYGGCHTSSRNiWFDKETCRTSCAHK 974
Cdd:cd22620     12 GKASFTRYYYNEESGKCETFIYGGVGGNSNN-FLTKEDCCKECAQG 56

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438676 Cd Length: 55 Bit Score: 36.36 E-value: 8.89e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872 1086 RYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:cd22633     20 RYYYNSSTRRCEKFRYGGC-GGNANNFHTLEECEKVC 55

bovine pancreatic trypsin inhibitor; This model contains bovine pancreatic trypsin inhibitor (BPTI, also known as pancreatic Kunitz inhibitor, aprotinin, or trypsin-kallikrein inhibitor), a small protein that inhibits the action of the trypsin, and is thus a member of the serine protease family of inhibitors. This class of enzymes contains conserved cysteine residues that form 3 disulfide bonds to stabilize the three-dimensional structure. BPTI has a relatively broad specificity, inhibiting trypsin as well as chymotrypsin, and elastase-like serine (pro)enzymes capable of very different primary specificity. It reacts rapidly with serine proteases to form stable complexes, but the enzyme:inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Furthermore, BPTI inhibits the nitric oxide synthase type-I and -II action, and impairs K+ transport by Ca2+-activated K+ channels. Clinically, BPTI is used in certain surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation since it significantly reduces hemorrhagic complications.

Pssm-ID: 438635 Cd Length: 52 Bit Score: 36.08 E-value: 9.14e-03

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1972288872   77 IKYYYDADSVQCKQFFYGGCKTTSRNFFAD---LQTC 110
Cdd:cd22592     16 IRYFYNAKSGLCETFVYGGCRAKRNNFLSAedcMRTC 52

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

Pssm-ID: 438649 Cd Length: 53 Bit Score: 36.18 E-value: 9.46e-03

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1972288872 1076 PCgdgKSWSNRYFYDKDTRSCRMFWSNGCfSSSKNNFDDLETCQWKC 1122
Cdd:cd22606     10 PC---KAWEPRWAYNSLLKQCQSFVYGGC-EGNENNFESKEACEDAC 52