E2 domain of amyloid precursor protein; The E2 domain is the largest of the conserved domains of the amyloid precursor protein. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures.E 2 can reversibly dimerize in solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulfate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    366 TTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKAD-------KKAVIQHFQEK 438
Cdd:pfam12925   1 TTTPPPTDAVDPYFEHPDPRNEHESFKKAKKRLEEKHRERMTKVMKEWEEAEERYQNLPKADpkaaekfKKAMTARFQET 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    439 VESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMV 518
Cdd:pfam12925  81 VEALEEEAAAERQQLVETHQQRVEAHLNDRRRDALECYLQALQENPPNPHRILKALKKLLRAEQKDRRHTLRHYRHLLAS 160

                         170       180       190
                  ....*....|....*....|....*....|
gi 4502167    519 DPKKAAQIRSQVMTHLRVIYERMNQSLSLL 548
Cdd:pfam12925 161 DPEKAEQMKPQVLTHLRVIDRRMNQSLTLL 190

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 4502167  294 QAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22607   5 QAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

E2 domain of amyloid precursor protein; The E2 domain is the largest of the conserved domains of the amyloid precursor protein. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures.E 2 can reversibly dimerize in solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulfate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    366 TTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKAD-------KKAVIQHFQEK 438
Cdd:pfam12925   1 TTTPPPTDAVDPYFEHPDPRNEHESFKKAKKRLEEKHRERMTKVMKEWEEAEERYQNLPKADpkaaekfKKAMTARFQET 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    439 VESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMV 518
Cdd:pfam12925  81 VEALEEEAAAERQQLVETHQQRVEAHLNDRRRDALECYLQALQENPPNPHRILKALKKLLRAEQKDRRHTLRHYRHLLAS 160

                         170       180       190
                  ....*....|....*....|....*....|
gi 4502167    519 DPKKAAQIRSQVMTHLRVIYERMNQSLSLL 548
Cdd:pfam12925 161 DPEKAEQMKPQVLTHLRVIDRRMNQSLTLL 190

juxtamembrane and transmembrane (JMTM) domain found in amyloid-like protein 2 (APLP-2) and similar proteins; Amyloid-like protein 2 (APLP-2), also called amyloid protein homolog (APPH), or CDEI box-binding protein (CDEBP), may play a role in the regulation of hemostasis. Its soluble form may have inhibitory properties towards coagulation factors. APLP-2 may bind to the DNA 5'-GTCACATG-3'(CDEI box). It inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein. This model corresponds to juxtamembrane and transmembrane (JMTM) domain of APLP-2, which consists of the intact transmembrane (TM) domain with adjacent N-terminal juxtamembrane (JM) region.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4502167  693 EDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQ 767
Cdd:cd21709   7 DDFSFSSSALIGLLVIAVAIATVIVISLVLLRKRQYGTISHGIVEVDPMLTPEERHLNKMQNHGYENPTYKYLEQ 81

Beta-amyloid precursor protein C-terminus; This is the amyloid, C-terminal, protein of the beta-Amyloid precursor protein (APP) which is a conserved and ubiquitous transmembrane glycoprotein strongly implicated in the pathogenesis of Alzheimer's disease but whose normal biological function is unknown. The C-terminal 100 residues are released and aggregate into amyloid deposits which are strongly implicated in the pathology of Alzheimer's disease plaque-formation. The domain is associated with family A4_EXTRA, pfam02177, further towards the N-terminus.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 4502167    716 IVITLVMLKKK-QYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFE 766
Cdd:pfam10515   1 IVVGMALLRRRaARSPSAHGFVEVDPNVTPEERHVANMQVNGYENPTYKYFE 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.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 4502167     295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:smart00131   7 PDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

E2 domain of amyloid precursor protein; The E2 domain is the largest of the conserved domains of the amyloid precursor protein. The structure of E2 consists of two coiled-coil sub-structures connected through a continuous helix, and bears an unexpected resemblance to the spectrin family of protein structures.E 2 can reversibly dimerize in solution, and the dimerization occurs along the longest dimension of the molecule in an antiparallel orientation, which enables the N-terminal substructure of one monomer to pack against the C-terminal substructure of a second monomer. The high degree of conservation of residues at the putative dimer interface suggests that the E2 dimer observed in the crystal could be physiologically relevant. Heparin sulfate proteoglycans, the putative ligands for the precursor present in extracellular matrix, bind to E2 at a conserved and positively charged site near the dimer interface.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    366 TTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKAD-------KKAVIQHFQEK 438
Cdd:pfam12925   1 TTTPPPTDAVDPYFEHPDPRNEHESFKKAKKRLEEKHRERMTKVMKEWEEAEERYQNLPKADpkaaekfKKAMTARFQET 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    439 VESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMV 518
Cdd:pfam12925  81 VEALEEEAAAERQQLVETHQQRVEAHLNDRRRDALECYLQALQENPPNPHRILKALKKLLRAEQKDRRHTLRHYRHLLAS 160

                         170       180       190
                  ....*....|....*....|....*....|
gi 4502167    519 DPKKAAQIRSQVMTHLRVIYERMNQSLSLL 548
Cdd:pfam12925 161 DPEKAEQMKPQVLTHLRVIDRRMNQSLTLL 190

juxtamembrane and transmembrane (JMTM) domain found in amyloid-like protein 2 (APLP-2) and similar proteins; Amyloid-like protein 2 (APLP-2), also called amyloid protein homolog (APPH), or CDEI box-binding protein (CDEBP), may play a role in the regulation of hemostasis. Its soluble form may have inhibitory properties towards coagulation factors. APLP-2 may bind to the DNA 5'-GTCACATG-3'(CDEI box). It inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein. This model corresponds to juxtamembrane and transmembrane (JMTM) domain of APLP-2, which consists of the intact transmembrane (TM) domain with adjacent N-terminal juxtamembrane (JM) region.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4502167  693 EDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQ 767
Cdd:cd21709   7 DDFSFSSSALIGLLVIAVAIATVIVISLVLLRKRQYGTISHGIVEVDPMLTPEERHLNKMQNHGYENPTYKYLEQ 81

Copper-binding of amyloid precursor, CuBD; This short domain, part of the extra-cellular N-terminus of the amyloid precursor protein, APP, can bind both copper and zinc, CuBD. The structure of Cu2+-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. The structure of Cu+-bound CuBD is almost identical to the Cu2+-bound structure except for the loss of one of the water ligands. The geometry of the site is unfavourable for Cu+, thus providing a mechanism by which CuBD could readily transfer Cu ions to other proteins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 4502167    133 CKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCP 188
Cdd:pfam12924   1 CKFDHKHNMDVCESHQHWHATAKEACAARGMVLHSFGMLLPCGIDLFTGVEFVCCP 56

Beta-amyloid precursor protein C-terminus; This is the amyloid, C-terminal, protein of the beta-Amyloid precursor protein (APP) which is a conserved and ubiquitous transmembrane glycoprotein strongly implicated in the pathogenesis of Alzheimer's disease but whose normal biological function is unknown. The C-terminal 100 residues are released and aggregate into amyloid deposits which are strongly implicated in the pathology of Alzheimer's disease plaque-formation. The domain is associated with family A4_EXTRA, pfam02177, further towards the N-terminus.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 4502167    716 IVITLVMLKKK-QYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFE 766
Cdd:pfam10515   1 IVVGMALLRRRaARSPSAHGFVEVDPNVTPEERHVANMQVNGYENPTYKYFE 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
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd00109   5 PDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22624   7 VTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22622   7 RVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22638   6 ETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 4502167  297 TGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22592   8 TGPCKARIIRYFYNAKSGLCETFVYGGCRAKRNNFLSAEDCMRTC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22603   7 SETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 4502167  297 TGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22623  12 VGPCRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSAC 56

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22632   9 ARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTC 54

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 4502167  294 QAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22613   7 KADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNENRFETLEECKKTC 54

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
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22600   6 AESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELAC 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
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22637   5 KDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22608   8 ADPGPCKAYIPRFYYNSASNKCQQFIYGGCKGNANNFETKDECRYTC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 4502167  298 GPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22633  12 GGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22604  10 ADSGPCFAYFPMWWYNVKTGQCEEFIYGGCQGNDNRYETEEECEKTC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22631   6 DAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22630   8 DEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22602   5 SKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22594   9 ADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

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 4502167  298 GPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22606   9 GPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTegKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22598   7 SDRGRCKASFERWYFNGR--TCAKFIYGGCGGNDNKFPTQEACMKRC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 4502167  298 GPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22626   8 GVGKAYIPRWYFNTSNARCEMFIFGGIGGNKNNFETLEECKKTC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22627   8 DEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 4502167  295 AETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22595   8 VRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 4502167  298 GPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22634  14 ISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 4502167  296 ETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVC 341
Cdd:cd22619  12 DTKRCKRVVRAFYYNPSAKTCLQFVYGGCNGNGNHFKSKALCRCHC 57

Trichohyalin-plectin-homology domain; This family is a mixtrue of two different families of eukaryotic proteins. Trichoplein or mitostatin, was first defined as a meiosis-specific nuclear structural protein. It has since been linked with mitochondrial movement. It is associated with the mitochondrial outer membrane, and over-expression leads to reduction in mitochondrial motility whereas lack of it enhances mitochondrial movement. The activity appears to be mediated through binding the mitochondria to the actin intermediate filaments (IFs). The family is in the trichohyalin-plectin-homology domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167    384 DENEHAHFQKAKERLEAKHRERMS------QVMREWEEAERQAKNLPKADKKAVIQHFQEKVEsLEQEAANERQQLVETH 457
Cdd:pfam13868 213 EEQERKERQKEREEAEKKARQRQElqqareEQIELKERRLAEEAEREEEEFERMLRKQAEDEE-IEQEEAEKRRMKRLEH 291

                          90
                  ....*....|....*..
gi 4502167    458 MARVEAMLNDRRRLALE 474
Cdd:pfam13868 292 RRELEKQIEEREEQRAA 308

F0F1 ATP synthase subunit B; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4502167   363 KLPTTAASTPDAVDKYLETPGDEnehahfqkaKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESL 442
Cdd:PRK14475  30 VLPKALAGALDAYAAKIQAELDE---------AQRLREEAQALLADVKAEREEAERQAAAMLAAAKADARRMEAEAKEKL 100

                         90       100
                 ....*....|....*....|.
gi 4502167   443 EqEAANERQQLVETHMARVEA 463
Cdd:PRK14475 101 E-EQIKRRAEMAERKIAQAEA 120