Spondin_N; This conserved region is found at the in the N-terminal half of several Spondin proteins. Spondins are involved in patterning axonal growth trajectory through either inhibiting or promoting adhesion of embryonic nerve cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253   197 AQYDLEFTGIWSKNTHPKDYPTleHLTHFTDMLGSSHSSNYSLWTIGGISTDGMKEIAEWGNTYKAEAEAKAKASEVRSL 276
Cdd:pfam06468   1 AKYELTFEGLWSRTTHPKDYPL--WRPHWSDLIGASHSSDYRLWEYGQYASEGVKQFAEWGSTKKLETELKAKSDSVRTI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253   277 MKVKGLWfPDVQGTTKSQFVVNKYHHFVSLATMFGPSPDWCVGLSSVNLCLPDCTWAEERTFELQPFDAGTDSGPTYMSP 356
Cdd:pfam06468  79 IKAPGIW-PNGTGKTSAEFRVDRNHHLVSLVSMIGPSPDWFVGVDSLNLCLKNCTWIDSVTLDLYPWDAGTDSGFTYTSP 157

                         170       180       190
                  ....*....|....*....|....*....|....
gi 32564253   357 NEPTEPREPIHWITTK--LNPLSPFYNSKSDTIP 388
Cdd:pfam06468 158 NFPTIPQEPIRRITSSypNHPASPFYYPNGKSLP 191

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 32564253   621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:pfam00014   1 ICSLPPDSGPCKASIPRWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTC 52

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 32564253   559 CKTTAWSDWSPCSASCDEGVRVRTR--LFFYSEHEKRCmhVNLQEKDTCVMQSC 610
Cdd:pfam19028   1 CVVSEWSEWSECSVTCGGGVQTRTRtvIVEPQNGGRPC--PELLERRPCNLPPC 52

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 32564253    435 MTQWEPWSLCSATCGKGIRIRSRVYVFPIKAQVF-HCHRQTTEKQFCN 481
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGgPCTGEDVETRACN 48

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 32564253    766 VGPWSRWSPCSVSCGEGSQTrRRRVVRARNDDWEEIECDDAETEVRQCTGR 816
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQT-RTRSCCSPPPQNGGGPCTGEDVETRACNEQ 50

Spondin_N; This conserved region is found at the in the N-terminal half of several Spondin proteins. Spondins are involved in patterning axonal growth trajectory through either inhibiting or promoting adhesion of embryonic nerve cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253   197 AQYDLEFTGIWSKNTHPKDYPTleHLTHFTDMLGSSHSSNYSLWTIGGISTDGMKEIAEWGNTYKAEAEAKAKASEVRSL 276
Cdd:pfam06468   1 AKYELTFEGLWSRTTHPKDYPL--WRPHWSDLIGASHSSDYRLWEYGQYASEGVKQFAEWGSTKKLETELKAKSDSVRTI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253   277 MKVKGLWfPDVQGTTKSQFVVNKYHHFVSLATMFGPSPDWCVGLSSVNLCLPDCTWAEERTFELQPFDAGTDSGPTYMSP 356
Cdd:pfam06468  79 IKAPGIW-PNGTGKTSAEFRVDRNHHLVSLVSMIGPSPDWFVGVDSLNLCLKNCTWIDSVTLDLYPWDAGTDSGFTYTSP 157

                         170       180       190
                  ....*....|....*....|....*....|....
gi 32564253   357 NEPTEPREPIHWITTK--LNPLSPFYNSKSDTIP 388
Cdd:pfam06468 158 NFPTIPQEPIRRITSSypNHPASPFYYPNGKSLP 191

spondin domain;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253  197 AQYDLEFTGIWSKNThpkdyptlehlTHFTDMLGSSHSSNYSLWTIGGISTDGMKEIAEWGNTYKAEAEAKAKASEVRSL 276
Cdd:NF038123   1 ATYTVTITNLTPPNG-----------QPFSPLVVAAHNGNFDLFEVGEPASEGLERLAEGGDPSGLLSALADQAGVVVVA 69

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253  277 MKVKGLWFPDVQGTTKSQFVVNKyHHFVSLATMFGPSPDWCVGLSSVNLCLPDCtwAEERTFELQPFDAGTDSGPTYM-- 354
Cdd:NF038123  70 VPGGGPLAPGASESVSFTFEAAD-GDYLSLATMLVPSNDWFVGLDSLDLFDLAG--GGTVTLSLNAYDAGTEANDEPEvn 146

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 32564253  355 ------------SPNEPTEPREPIHWITTKL------NPLSPFYNSKSDTIPTLAKVILRRK 398
Cdd:NF038123 147 ipgpagggegfnGAGPDTDENGVVAIHPGVPgdddadGGISDVLNPNHRFDNPVAKVVITRT 208

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 32564253   621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd00109   1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 32564253    708 VSKWTAWGSCSVSCGRGKKSRSRHVVK-LARNGGHQCSEHLMQELQCRLRPCP 759
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSpPPQNGGGPCTGEDVETRACNEQPCP 53

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 32564253   497 CQVSSWGSWGECSVQCGHGMRSRNRTFLNPATKSG-DCSVDLERKDiCVGEN 547
Cdd:pfam19028   1 CVVSEWSEWSECSVTCGGGVQTRTRTVIVEPQNGGrPCPELLERRP-CNLPP 51

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20
                  ....*....|....*....|....*
gi 32564253   433 CMMTQWEPWSLCSATCGKGIRIRSR 457
Cdd:pfam19028   1 CVVSEWSEWSECSVTCGGGVQTRTR 25

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20
                  ....*....|....*....|..
gi 32564253   764 CQVGPWSRWSPCSVSCGEGSQT 785
Cdd:pfam19028   1 CVVSEWSEWSECSVTCGGGVQT 22

sporozoite surface protein 2 (SSP2); Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 32564253  695 TEVddggERV-DCEVskWTAWGSCSVSCGRGKKSRSRHVVklarnggHQ-CSEHLMQElqCRLRPCPVK 761
Cdd:PTZ00441 232 TEV----ERTaSCGP--WDEWTPCSVTCGKGTHSRSRPIL-------HEgCTTHMVEE--CEEEECPVE 285

sporozoite surface protein 2 (SSP2); Provisional

                         10        20
                 ....*....|....*....|....*.
gi 32564253  760 VKLTCQVGPWSRWSPCSVSCGEGSQT 785
Cdd:PTZ00441 234 VERTASCGPWDEWTPCSVTCGKGTHS 259

Spondin_N; This conserved region is found at the in the N-terminal half of several Spondin proteins. Spondins are involved in patterning axonal growth trajectory through either inhibiting or promoting adhesion of embryonic nerve cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253   197 AQYDLEFTGIWSKNTHPKDYPTleHLTHFTDMLGSSHSSNYSLWTIGGISTDGMKEIAEWGNTYKAEAEAKAKASEVRSL 276
Cdd:pfam06468   1 AKYELTFEGLWSRTTHPKDYPL--WRPHWSDLIGASHSSDYRLWEYGQYASEGVKQFAEWGSTKKLETELKAKSDSVRTI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253   277 MKVKGLWfPDVQGTTKSQFVVNKYHHFVSLATMFGPSPDWCVGLSSVNLCLPDCTWAEERTFELQPFDAGTDSGPTYMSP 356
Cdd:pfam06468  79 IKAPGIW-PNGTGKTSAEFRVDRNHHLVSLVSMIGPSPDWFVGVDSLNLCLKNCTWIDSVTLDLYPWDAGTDSGFTYTSP 157

                         170       180       190
                  ....*....|....*....|....*....|....
gi 32564253   357 NEPTEPREPIHWITTK--LNPLSPFYNSKSDTIP 388
Cdd:pfam06468 158 NFPTIPQEPIRRITSSypNHPASPFYYPNGKSLP 191

spondin domain;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253  197 AQYDLEFTGIWSKNThpkdyptlehlTHFTDMLGSSHSSNYSLWTIGGISTDGMKEIAEWGNTYKAEAEAKAKASEVRSL 276
Cdd:NF038123   1 ATYTVTITNLTPPNG-----------QPFSPLVVAAHNGNFDLFEVGEPASEGLERLAEGGDPSGLLSALADQAGVVVVA 69

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 32564253  277 MKVKGLWFPDVQGTTKSQFVVNKyHHFVSLATMFGPSPDWCVGLSSVNLCLPDCtwAEERTFELQPFDAGTDSGPTYM-- 354
Cdd:NF038123  70 VPGGGPLAPGASESVSFTFEAAD-GDYLSLATMLVPSNDWFVGLDSLDLFDLAG--GGTVTLSLNAYDAGTEANDEPEvn 146

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 32564253  355 ------------SPNEPTEPREPIHWITTKL------NPLSPFYNSKSDTIPTLAKVILRRK 398
Cdd:NF038123 147 ipgpagggegfnGAGPDTDENGVVAIHPGVPgdddadGGISDVLNPNHRFDNPVAKVVITRT 208

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 32564253   621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd00109   1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 32564253   706 CEVSKWTAWGSCSVSCGRGKKSRSRHVVKLARNGGHQCSEhLMQELQCRLRPC 758
Cdd:pfam19028   1 CVVSEWSEWSECSVTCGGGVQTRTRTVIVEPQNGGRPCPE-LLERRPCNLPPC 52

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 32564253 621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22614   4 FCFLEEDPGICRGLITRYFYNNQSKQCERFKYGGCLGNQNNFESLEECQNTC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 32564253 620 EICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22603   1 EDCLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 32564253 620 EICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22611   1 DVCSLPKESGPCMAYFPRWWYDKETNTCSKFIYGGCQGNNNNFQSEAICQNIC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 32564253 621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22633   4 ICLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22609   2 CLEPKVVGVCKASMTRYFYNAQTGHCEQFVYGGCGGNRNNFLTLEDCMKTC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 32564253 621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22615   3 FCLSPKDEGLCSASVTRYYYNSATKTCEPFNYTGCGGNNNNFTSKKDCLRVC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 32564253 620 EICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22599   4 GICRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKAC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 32564253 620 EICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22596   1 DSCKLPPDAGPCFGMIQRYFYNSSSMACQTFNYGGCLGNQNNFVTEKECLQTC 53

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22624   2 CTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETC 52

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22592   2 CLEPPYTGPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22637   1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQICLPG 675
Cdd:cd22620   3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKECAQG 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 32564253 621 ICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQICLP 674
Cdd:cd22630   2 ACSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALCVK 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 32564253 620 EICQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22629   1 DICKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQICLP 674
Cdd:cd22600   2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELACLR 54

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 32564253 629 GQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22606   9 GPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22628   1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22639   1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 32564253 622 CQEDKQAGQCAGNFPRYWYNHEKTQCERFIFTGCKGNRNQFETEEECKQIC 672
Cdd:cd22638   1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 32564253   497 CQVSSWGSWGECSVQCGHGMRSRNRTFLNPATKSG-DCSVDLERKDiCVGEN 547
Cdd:pfam19028   1 CVVSEWSEWSECSVTCGGGVQTRTRTVIVEPQNGGrPCPELLERRP-CNLPP 51