Linking region between Kunitz_BPTI and I-set on papilin; Papilin_u7 is a conserved region of natively unstructured residues on proteoglycan-like sulfated glycoprotein - papilin 0 in higher eukaryotes. It links the Kunitz_BPTI, pfam00014, and I-set domains pfam07679. The function is not known.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  841 PQPGASGRSTHTDGGGSSPAGEQEPSQHRTGAAVQRKPWPSGGLWRQDQQPGPGEAPHTQAFGEWPWGQELGSRAPGLGG 920
Cdd:pfam16626    1 PEPGASGQSTHTDGGGSGPGGQQEASWHRTGATVQRKPLPSGGLWRRDQEPGPGEAPHTQAFGERPWGQELGPRAPGLGG 80

                           90
                   ....*....|..
gi 2217298798  921 DAGSPAPPFHSS 932
Cdd:pfam16626   81 DAGRPAPPSHSS 92

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2217298798  781 CLLPS-AHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22635      1 CLLDKdAGTVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 2217298798  393 WKAGPWAPCSASCGGGSQSRSVYCISSDGagiQEAVEEAECAGLPgKPPAIQACNLQRC 451
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGG---GSIVPDSECSAQK-KPPETQSCNLKPC 55

ADAMTS cysteine-rich domain; This cysteine rich domain is found in a variety of ADAMTS and ADAMTS-like endopeptidases widely spread in animals. It is a well-conserved cysteine-rich sequence containing 10 cysteine residues. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase, pfam08516) and consists of at least 20 members sharing a high degree of sequence similarity and conserved domain organization. Members of the ADAMTS family have been implicated in a range of diseases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  112 DFRAEQCAEFDGAEFQGRR-----YRW---LPYYSAPNKCELNCIPKGENFYYKHREAVVDGTPCEP------GKRDVCV 177
Cdd:pfam19236    4 EFMSQQCARTDGQPLRSSPggasfYHWgaaVPHSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPsgpredGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 2217298798  178 DGSCRVVGCDHELDSSKQEDKCLRCGGDGTTC 209
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2217298798  454 WSPEPWGECSVSCGVGVRKRSVTCRGERG-SLLHTAACSLEDRPPLTEPCVHEDC 507
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGgSIVPDSECSAQKKPPETQSCNLKPC 55

PLAC (protease and lacunin) domain; The PLAC (protease and lacunin) domain is a short six-cysteine region that is usually found at the C terminal of proteins. It is found in a range of proteins including PACE4 (paired basic amino acid cleaving enzyme 4) and the extracellular matrix protein lacunin.

                           10        20        30
                   ....*....|....*....|....*....|...
gi 2217298798 1183 CVDQpeLANCDLILQAQLCGNEYYSSFCCASCS 1215
Cdd:pfam08686    1 CKDK--FANCSLVVQARLCSHKYYRQFCCRSCS 31

Linking region between Kunitz_BPTI and I-set on papilin; Papilin_u7 is a conserved region of natively unstructured residues on proteoglycan-like sulfated glycoprotein - papilin 0 in higher eukaryotes. It links the Kunitz_BPTI, pfam00014, and I-set domains pfam07679. The function is not known.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  841 PQPGASGRSTHTDGGGSSPAGEQEPSQHRTGAAVQRKPWPSGGLWRQDQQPGPGEAPHTQAFGEWPWGQELGSRAPGLGG 920
Cdd:pfam16626    1 PEPGASGQSTHTDGGGSGPGGQQEASWHRTGATVQRKPLPSGGLWRRDQEPGPGEAPHTQAFGERPWGQELGPRAPGLGG 80

                           90
                   ....*....|..
gi 2217298798  921 DAGSPAPPFHSS 932
Cdd:pfam16626   81 DAGRPAPPSHSS 92

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2217298798  781 CLLPS-AHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22635      1 CLLDKdAGTVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 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        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 2217298798   780 RCLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:smart00131    2 VCLLPPDTGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  1077 PRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQPVssprngLPVQADGHRVHQSPDGTLLIYNLRARDEGSYTCSAYQGS 1156
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGKL------LAESGRFSVSRSGSTSTLTISNVTPEDSGTYTCAATNSS 74

                            90
                    ....*....|.
gi 2217298798  1157 QAVSRSTEVKV 1167
Cdd:smart00410   75 GSASSGTTLTV 85

Fifth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798 1085 GQRIRMTCRAEGFPPPAIEWQRDGQPvssprngLPVqadGHRVHQSPDGTLLIYNL-RARDEGSYTCSAY-QGSQAVSRS 1162
Cdd:cd20958     15 GQTLRLHCPVAGYPISSITWEKDGRR-------LPL---NHRQRVFPNGTLVIENVqRSSDEGEYTCTARnQQGQSASRS 84

                   ....*
gi 2217298798 1163 TEVKV 1167
Cdd:cd20958     85 VFVKV 89

ADAMTS cysteine-rich domain; This cysteine rich domain is found in a variety of ADAMTS and ADAMTS-like endopeptidases widely spread in animals. It is a well-conserved cysteine-rich sequence containing 10 cysteine residues. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase, pfam08516) and consists of at least 20 members sharing a high degree of sequence similarity and conserved domain organization. Members of the ADAMTS family have been implicated in a range of diseases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  112 DFRAEQCAEFDGAEFQGRR-----YRW---LPYYSAPNKCELNCIPKGENFYYKHREAVVDGTPCEP------GKRDVCV 177
Cdd:pfam19236    4 EFMSQQCARTDGQPLRSSPggasfYHWgaaVPHSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPsgpredGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 2217298798  178 DGSCRVVGCDHELDSSKQEDKCLRCGGDGTTC 209
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  943 PSLVQAALGQLVRLSCSDDTAPESQAAWQKDGQPI-SSDRHRLQFDG---SLIIHPLQAEDAGTYSCGSTRP-GRDSQKI 1017
Cdd:pfam07679    7 PKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrSSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVATNSaGEAEASA 86

                   ..
gi 2217298798 1018 QL 1019
Cdd:pfam07679   87 EL 88

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798   943 PSLVQAALGQLVRLSCSDDTAPESQAAWQKDGQ--PISSDRHRLQFDG---SLIIHPLQAEDAGTYSC-GSTRPGRDSQK 1016
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCaATNSSGSASSG 80

                    ....*
gi 2217298798  1017 IQLRI 1021
Cdd:smart00410   81 TTLTV 85

PLAC (protease and lacunin) domain; The PLAC (protease and lacunin) domain is a short six-cysteine region that is usually found at the C terminal of proteins. It is found in a range of proteins including PACE4 (paired basic amino acid cleaving enzyme 4) and the extracellular matrix protein lacunin.

                           10        20        30
                   ....*....|....*....|....*....|...
gi 2217298798 1183 CVDQpeLANCDLILQAQLCGNEYYSSFCCASCS 1215
Cdd:pfam08686    1 CKDK--FANCSLVVQARLCSHKYYRQFCCRSCS 31

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|..
gi 2217298798   515 WHVGTWGLCSKSCSSGTRRRQVICAIGPPSHCGSLQHSKPVDVEPCNTQPCH 566
Cdd:smart00209    2 SEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPCP 53

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 2217298798   451 CAAWSPepWGECSVSCGVGVRKRSVTCRGERGSlLHTAACSLEDrpPLTEPCVHEDCP 508
Cdd:smart00209    1 WSEWSE--WSPCSVTCGGGVQTRTRSCCSPPPQ-NGGGPCTGED--VETRACNEQPCP 53

Linking region between Kunitz_BPTI and I-set on papilin; Papilin_u7 is a conserved region of natively unstructured residues on proteoglycan-like sulfated glycoprotein - papilin 0 in higher eukaryotes. It links the Kunitz_BPTI, pfam00014, and I-set domains pfam07679. The function is not known.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798  841 PQPGASGRSTHTDGGGSSPAGEQEPSQHRTGAAVQRKPWPSGGLWRQDQQPGPGEAPHTQAFGEWPWGQELGSRAPGLGG 920
Cdd:pfam16626    1 PEPGASGQSTHTDGGGSGPGGQQEASWHRTGATVQRKPLPSGGLWRRDQEPGPGEAPHTQAFGERPWGQELGPRAPGLGG 80

                           90
                   ....*....|..
gi 2217298798  921 DAGSPAPPFHSS 932
Cdd:pfam16626   81 DAGRPAPPSHSS 92

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2217298798  781 CLLPS-AHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22635      1 CLLDKdAGTVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 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 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd00109      1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217298798 1076 QPRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQPVSSprnglpvqADGHRVHQSPD-GTLLIYNLRARDEGSYTCSAYQ 1154
Cdd:pfam07679    6 KPKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLRS--------SDRFKVTYEGGtYTLTISNVQPDDSGKYTCVATN 77

                           90
                   ....*....|...
gi 2217298798 1155 GSQAVSRSTEVKV 1167
Cdd:pfam07679   78 SAGEAEASAELTV 90

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 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22629      3 CKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22637      1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2217298798 1074 QNQPRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQPVSSPRnglpvqaDGHRVHQSPDGTLLIYNLRARDEGSYTCSA 1152
Cdd:pfam13927    5 TVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPISSGS-------TRSRSLSGSNSTLTISNVTRSDAGTYTCVA 76

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 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22628      1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 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        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2217298798  780 RCLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSCQG 833
Cdd:cd22624      1 RCTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCSG 54

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2217298798  335 WSHGSWSDCSAECGGGHQSRLVFCTI--DHEAYPDHMCQRQPRPADRRSCNLHPC 387
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQkgGGSIVPDSECSAQKKPPETQSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22631      1 CLLGQDAGSCQNYTMMWFFDSKQGRCSRFWYGGCGGNANRFETQEECENLC 51

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

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22606      2 CSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

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

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22616      5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of the Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit-2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

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gi 2217298798  941 VEPSLVQAALGQLVRLSCSDDTA-PESQAAWQKDGQPISSD--RHRLQFDGSLIIHPLQAEDAGTYSC 1005
Cdd:cd05724      2 VEPSDTQVAVGEMAVLECSPPRGhPEPTVSWRKDGQPLNLDneRVRIVDDGNLLIAEARKSDEGTYKC 69

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

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gi 2217298798 1088 IRMTCRAEGFPPPAIEWQRDGQPvssprngLPVQADGHRVHQSPDGTLLIYNLRARDEGSYTCSA 1152
Cdd:cd00096      1 VTLTCSASGNPPPTITWYKNGKP-------LPPSSRDSRRSELGNGTLTISNVTLEDSGTYTCVA 58

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.

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22622      3 CAAPRVTGPCRAAFPRWYYDPESQSCKEFIYGGCRGNKNNYLSEEECMDRC 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.

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSCQG 833
Cdd:cd22600      2 CKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELACLR 54

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

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22638      1 CTLKPETGPCRAYIEKWYYDPSTQSCKTFIYGGCGGNGNRFDSEEDCQETC 51

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

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gi 2217298798  454 WSPEPWGECSVSCGVGVRKRSVTCRGERG-SLLHTAACSLEDRPPLTEPCVHEDC 507
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGgSIVPDSECSAQKKPPETQSCNLKPC 55

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

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSCQG 833
Cdd:cd22599      6 CRLPADEGICRALIPRFYFNTETGQCTEFIYGGCGGNENNFETIEECEKACGA 58

Fourth immunoglobulin (Ig)-like domain of hemolin, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain of hemolin and similar proteins. Hemolin, an insect immunoglobulin superfamily (IgSF) member containing four Ig-like domains, is a lipopolysaccharide-binding immune protein induced during bacterial infection. Hemolin shares significant sequence similarity with the first four Ig-like domains of the transmembrane cell adhesion molecules (CAMs) of the L1 family. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. The fourth Ig-like domain of hemolin is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set domains, members of the I-set have a discontinuous A strand but lack a C" strand. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

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gi 2217298798 1074 QNQPRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQPVSSPRNglpvQADGHrvhqspDGTLLIYNLRARDEGSYTCSAY 1153
Cdd:cd20978      5 QKPEKNVVVKGGQDVTLPCQVTGVPQPKITWLHNGKPLQGPME----RATVE------DGTLTIINVQPEDTGYYGCVAT 74

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gi 2217298798 1154 QGSQAVSRSTEVKV 1167
Cdd:cd20978     75 NEIGDIYTETLLHV 88

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.

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gi 2217298798  781 CLLPSAHGSCADWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 831
Cdd:cd22602      1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

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