ADAM-TS Spacer 1; This domain represents the Spacer-1 region from the ADAM-TS and ADAM-TS-like proteins. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase) and is a subfamily of the metalloprotease family, sharing a high degree of sequence similarity and conserved domain organization among its members. Members of the ADAM-TS family have been implicated in a range of diseases. ADAM-TS-like proteins lack a metalloprotease domain. They resides in the ECM and have regulatory roles. Examples of ADAM-TS-like proteins are papilin and punctin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158711721   185 PVTGTFDGNdLSRGYNQIFIIPAGATSIRIEEAAASRNFLAVKSIRGEYYLNGHWTIEAA-QALPVASTVLQYERgveGD 263
Cdd:pfam05986    1 TVSGSFTEG-RAKGYVTFVTIPAGATHIHIVNRKPSFTHLAVKNVQGKYILNGKGSISLNpTYPSLLGTVLEYRR---SL 76

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 158711721   264 LAPERLQARGPTSEPLVIELLSQ---ESNPGVHYEYYLP 299
Cdd:pfam05986   77 PALEELHAPGPTQEDLEIQVLRQygkGTNPGITYEYFIP 115

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 158711721  750 CLLPS-AQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
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 158711721   367 WKVGPWTPCSVSCGGGVQSRSVYCISsdgTGGQEAAEETQCaGLVGKPPTTQACNLQHC 425
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQ---KGGGSIVPDSEC-SAQKKPPETQSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 158711721   309 WSHGSWGDCSAECGGGHQSRLVFCTI--DNEAYPDHMCQHQPRPTHRRSCNTQPC 361
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQkgGGSIVPDSECSAQKKPPETQSCNLKPC 55

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 158711721     30 WGTWGEWSPCSRTCGGGISFRERPCYS-QRRDGGTSCVGPARSHRTCHTESCP 81
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSpPPQNGGGPCTGEDVETRACNEQPCP 53

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 158711721   489 WHVGSWSLCSKSCGSGIRRRQVVCTIGPPGRCVDLQ----SSKPAEMEACNRQPC 539
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 158711721  1235 CIDQpeLANCALILQAQLCGNEYYSSFCCASCS 1267
Cdd:pfam08686    1 CKDK--FANCSLVVQARLCSHKYYRQFCCRSCS 31

ADAM-TS Spacer 1; This domain represents the Spacer-1 region from the ADAM-TS and ADAM-TS-like proteins. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase) and is a subfamily of the metalloprotease family, sharing a high degree of sequence similarity and conserved domain organization among its members. Members of the ADAM-TS family have been implicated in a range of diseases. ADAM-TS-like proteins lack a metalloprotease domain. They resides in the ECM and have regulatory roles. Examples of ADAM-TS-like proteins are papilin and punctin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158711721   185 PVTGTFDGNdLSRGYNQIFIIPAGATSIRIEEAAASRNFLAVKSIRGEYYLNGHWTIEAA-QALPVASTVLQYERgveGD 263
Cdd:pfam05986    1 TVSGSFTEG-RAKGYVTFVTIPAGATHIHIVNRKPSFTHLAVKNVQGKYILNGKGSISLNpTYPSLLGTVLEYRR---SL 76

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 158711721   264 LAPERLQARGPTSEPLVIELLSQ---ESNPGVHYEYYLP 299
Cdd:pfam05986   77 PALEELHAPGPTQEDLEIQVLRQygkGTNPGITYEYFIP 115

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 158711721  750 CLLPS-AQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
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 158711721    749 RCLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
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 158711721   1050 PGVVDASPGQRIRLTCRAEGFPVPTIEWQRDGQ--LVSSPRHQVQPDG---SLVISRVDVEDGGYYSCVAFNGQDRDQRW 1124
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 158711721   1125 VQLRV 1129
Cdd:smart00410   81 TTLTV 85

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 158711721   367 WKVGPWTPCSVSCGGGVQSRSVYCISsdgTGGQEAAEETQCaGLVGKPPTTQACNLQHC 425
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQ---KGGGSIVPDSEC-SAQKKPPETQSCNLKPC 55

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158711721   1139 PPAVTVAEGDTARLLCVVAG-ESVNIRWSRNGLPIQADGHRVHQSPDG---TLLIHNLRPRDEGSYTCSAFRGSQAVSRS 1214
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGsPPPEVTWYKQGGKLLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 158711721   1215 TEVKV 1219
Cdd:smart00410   81 TTLTV 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 158711721 1140 PAVTVAEGDTARLLCVVAGESV-NIRWSRNG--LPIqadGHRVHQSPDGTLLIHNL-RPRDEGSYTCSAF-RGSQAVSRS 1214
Cdd:cd20958     8 GNLTAVAGQTLRLHCPVAGYPIsSITWEKDGrrLPL---NHRQRVFPNGTLVIENVqRSSDEGEYTCTARnQQGQSASRS 84

                  ....*
gi 158711721 1215 TEVKV 1219
Cdd:cd20958    85 VFVKV 89

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 158711721     30 WGTWGEWSPCSRTCGGGISFRERPCYS-QRRDGGTSCVGPARSHRTCHTESCP 81
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSpPPQNGGGPCTGEDVETRACNEQPCP 53

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 158711721   489 WHVGSWSLCSKSCGSGIRRRQVVCTIGPPGRCVDLQ----SSKPAEMEACNRQPC 539
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPDSecsaQKKPPETQSCNLKPC 55

Thrombospondin type 1 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 158711721    33 WGEWSPCSRTCGGGISFRERPCySQRRDGGTSCVGPARSHRTCHTESC 80
Cdd:pfam00090    3 WSPWSPCSVTCGKGIQVRQRTC-KSPFPGGEPCTGDDIETQACKMDKC 49

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 158711721    911 PSLVQAAPGQAVQLFCPGNIPSEFQAGWQKEGR--PISSNRYQLQADG---SLIISRLRPEDAGIYSC 973
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTC 68

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*....
gi 158711721    367 WKVGPWTPCSVSCGGGVQSRSVYCISSDGTGGQEaaeetQCAGLvgkPPTTQACNLQHC 425
Cdd:smart00209    2 SEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGG-----PCTGE---DVETRACNEQPC 52

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*
gi 158711721    309 WSH-GSWGDCSAECGGGHQSRLVFCTIDNEAYPDHMCQHQPRptHRRSCNTQPCP 362
Cdd:smart00209    1 WSEwSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDV--ETRACNEQPCP 53

ADAM-TS Spacer 1; This domain represents the Spacer-1 region from the ADAM-TS and ADAM-TS-like proteins. ADAM-TS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) is closely related to the ADAM family (A Disintegrin and Metalloproteinase) and is a subfamily of the metalloprotease family, sharing a high degree of sequence similarity and conserved domain organization among its members. Members of the ADAM-TS family have been implicated in a range of diseases. ADAM-TS-like proteins lack a metalloprotease domain. They resides in the ECM and have regulatory roles. Examples of ADAM-TS-like proteins are papilin and punctin.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158711721   185 PVTGTFDGNdLSRGYNQIFIIPAGATSIRIEEAAASRNFLAVKSIRGEYYLNGHWTIEAA-QALPVASTVLQYERgveGD 263
Cdd:pfam05986    1 TVSGSFTEG-RAKGYVTFVTIPAGATHIHIVNRKPSFTHLAVKNVQGKYILNGKGSISLNpTYPSLLGTVLEYRR---SL 76

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 158711721   264 LAPERLQARGPTSEPLVIELLSQ---ESNPGVHYEYYLP 299
Cdd:pfam05986   77 PALEELHAPGPTQEDLEIQVLRQygkGTNPGITYEYFIP 115

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 158711721  750 CLLPS-AQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
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 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd00109     1 CLLPPDPGPCRAYFPRWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTCR 801
Cdd:cd22639     1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVCV 52

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd22629     3 CKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 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 158711721   1050 PGVVDASPGQRIRLTCRAEGFPVPTIEWQRDGQ--LVSSPRHQVQPDG---SLVISRVDVEDGGYYSCVAFNGQDRDQRW 1124
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 158711721   1125 VQLRV 1129
Cdd:smart00410   81 TTLTV 85

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 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd22628     1 CLEPLDPGPCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 158711721   367 WKVGPWTPCSVSCGGGVQSRSVYCISsdgTGGQEAAEETQCaGLVGKPPTTQACNLQHC 425
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQ---KGGGSIVPDSEC-SAQKKPPETQSCNLKPC 55

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158711721  1135 ITGLPPAVTVAEGDTARLLCVVAGESV-NIRWSRNGLPIQADGH-RVHQSPD-GTLLIHNLRPRDEGSYTCSAFRGSQAV 1211
Cdd:pfam07679    3 FTQKPKDVEVQEGESARFTCTVTGTPDpEVSWFKDGQPLRSSDRfKVTYEGGtYTLTISNVQPDDSGKYTCVATNSAGEA 82

                   ....*...
gi 158711721  1212 SRSTEVKV 1219
Cdd:pfam07679   83 EASAELTV 90

Immunoglobulin (Ig)-like domain of human titin C terminus and similar proteins; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth immunoglobulin (Ig)-like domain from the C-terminus of human titin x and similar proteins. Titin (also called connectin) is a fibrous sarcomeric protein specifically found in vertebrate striated muscle. Titin is gigantic; depending on isoform composition it ranges from 2970 to 3700 kDa, and is of a length that spans half a sarcomere. Titin largely consists of multiple repeats of Ig-like and fibronectin type 3 (FN-III)-like domains. Titin connects the ends of myosin thick filaments to Z disks and extends along the thick filament to the H zone and appears to function similar to an elastic band, keeping the myosin filaments centered in the sarcomere during muscle contraction or stretching. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 158711721 1039 PATRLrldrTQPGVVDASPGQRIRLTCRAEGFPVPTIEWQRDGQ-LVSSPRHQV---QPDGSLVISRVDVEDGGYYSCVA 1114
Cdd:cd05747     3 PATIL----TKPRSLTVSEGESARFSCDVDGEPAPTVTWMREGQiIVSSQRHQItstEYKSTFEISKVQMSDEGNYTVVV 78

                  ....*...
gi 158711721 1115 FNGQDRDQ 1122
Cdd:cd05747    79 ENSEGKQE 86

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.

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gi 158711721  749 RCLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTCRG 802
Cdd:cd22624     1 RCTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCSG 54

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

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gi 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd22630     3 CSLDQDEGECQNYVLKWYYDQEQKECSQFWYGGCGGNKNRFETQEECEALC 53

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

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gi 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd22606     2 CSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDAC 52

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.

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gi 158711721 1140 PAVTVAEGDTARLLCVVAGESV-NIRWSRNG--LPIqadGHRVHQSPDGTLLIHNL-RPRDEGSYTCSAF-RGSQAVSRS 1214
Cdd:cd20958     8 GNLTAVAGQTLRLHCPVAGYPIsSITWEKDGrrLPL---NHRQRVFPNGTLVIENVqRSSDEGEYTCTARnQQGQSASRS 84

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gi 158711721 1215 TEVKV 1219
Cdd:cd20958    85 VFVKV 89

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 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd22616     5 CLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

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

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gi 158711721  750 CLLPSAQGSCGDWAARWYFVASVGRCNRFWYGGCHGNANNFASEQECMNTC 800
Cdd:cd22633     5 CLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55