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 1476587899  798 PQPGASGRSTHTDGGGSSPAGEQEPSQHRTGAAVQRKPWPSGGLWRQDQQPGPGEAPHTQAFGEWPWGQELGSRAPGLGG 877
Cdd:pfam16626    1 PEPGASGQSTHTDGGGSGPGGQQEASWHRTGATVQRKPLPSGGLWRRDQEPGPGEAPHTQAFGERPWGQELGPRAPGLGG 80

                           90
                   ....*....|..
gi 1476587899  878 DAGSPAPPFHSS 889
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
                   ....*....|....*....|....*....|....*....|
gi 1476587899  749 DWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 788
Cdd:cd22635     13 DYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1476587899  1123 PPTVTVPEGDTARLLCVVAG-ESVNIRWSRNGLPVQADGHRVHQSPDG---TLLIYNLRARDEGSYTCSAYQGSQAVSRS 1198
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGsPPPEVTWYKQGGKLLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 1476587899  1199 TEVKV 1203
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 1476587899  308 WSHGSWSDCSAECGGGHQSRLVFCTI--DHEAYPDHMCQRQPRPADRRSCNLHPC 360
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 1476587899    29 WGPWSQWSPCSRTCGGGVSFRERPCYS-QRRDGGSSCVGPARSHRSCRTESCP 80
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 1476587899  427 WSPEPWGECSVSCGVGVRKRSVTCRGERG-SLLHTAACSLEDRPPLTEPCVHEDC 480
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 1476587899 1219 CVDQpeLANCDLILQAQLCGNEYYSSFCCASCS 1251
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 1476587899  798 PQPGASGRSTHTDGGGSSPAGEQEPSQHRTGAAVQRKPWPSGGLWRQDQQPGPGEAPHTQAFGEWPWGQELGSRAPGLGG 877
Cdd:pfam16626    1 PEPGASGQSTHTDGGGSGPGGQQEASWHRTGATVQRKPLPSGGLWRRDQEPGPGEAPHTQAFGERPWGQELGPRAPGLGG 80

                           90
                   ....*....|..
gi 1476587899  878 DAGSPAPPFHSS 889
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
                   ....*....|....*....|....*....|....*....|
gi 1476587899  749 DWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 788
Cdd:cd22635     13 DYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

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

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 1476587899  753 RWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSCQ 789
Cdd:pfam00014   17 RWYYNPTTGTCEPFTYGGCGGNANNFESLEECESTCR 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 1476587899  1123 PPTVTVPEGDTARLLCVVAG-ESVNIRWSRNGLPVQADGHRVHQSPDG---TLLIYNLRARDEGSYTCSAYQGSQAVSRS 1198
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGsPPPEVTWYKQGGKLLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 1476587899  1199 TEVKV 1203
Cdd:smart00410   81 TTLTV 85

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1476587899 1119 ISGLPPTVTVPEGDTARLLCVVAGESV-NIRWSRNGLPVQADGH-RVHQSPD-GTLLIYNLRARDEGSYTCSAYQGSQAV 1195
Cdd:pfam07679    3 FTQKPKDVEVQEGESARFTCTVTGTPDpEVSWFKDGQPLRSSDRfKVTYEGGtYTLTISNVQPDDSGKYTCVATNSAGEA 82

                   ....*...
gi 1476587899 1196 SRSTEVKV 1203
Cdd:pfam07679   83 EASAELTV 90

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1476587899  308 WSHGSWSDCSAECGGGHQSRLVFCTI--DHEAYPDHMCQRQPRPADRRSCNLHPC 360
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQkgGGSIVPDSECSAQKKPPETQSCNLKPC 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 1476587899   85 DFRAEQCAEFDGAEFQGRR-----YRW---LPYYSAPNKCELNCIPKGENFYYKHREAVVDGTPCEP------GKRDVCV 150
Cdd:pfam19236    4 EFMSQQCARTDGQPLRSSPggasfYHWgaaVPHSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPsgpredGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 1476587899  151 DGSCRVVGCDHELDSSKQEDKCLRCGGDGTTC 182
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1476587899    29 WGPWSQWSPCSRTCGGGVSFRERPCYS-QRRDGGSSCVGPARSHRSCRTESCP 80
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSpPPQNGGGPCTGEDVETRACNEQPCP 53

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1476587899  900 PSLVQAALGQLVRLSCSDDTAPESQAAWQKDGQPI-SSDRHRLQFDG---SLIIHPLQAEDAGTYSCGSTRP-GRDSQKI 974
Cdd:pfam07679    7 PKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrSSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVATNSaGEAEASA 86

                   ..
gi 1476587899  975 QL 976
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 1476587899   900 PSLVQAALGQLVRLSCSDDTAPESQAAWQKDGQ--PISSDRHRLQFDG---SLIIHPLQAEDAGTYSC-GSTRPGRDSQK 973
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCaATNSSGSASSG 80

                    ....*
gi 1476587899   974 IQLRI 978
Cdd:smart00410   81 TTLTV 85

Thrombospondin type 1 domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1476587899   30 GPWSQWSPCSRTCGGGVSFRERPCySQRRDGGSSCVGPARSHRSCRTESC 79
Cdd:pfam00090    1 SPWSPWSPCSVTCGKGIQVRQRTC-KSPFPGGEPCTGDDIETQACKMDKC 49

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*
gi 1476587899   308 WSH-GSWSDCSAECGGGHQSRLVFCTIDHEAYPDHMCQRQPRpaDRRSCNLHPCP 361
Cdd:smart00209    1 WSEwSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDV--ETRACNEQPCP 53

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*.
gi 1476587899   369 GPWAPCSASCGGGSQSRSVYCISSdgagiQEAVEEAECaglPGKPPAIQACNLQRC 424
Cdd:smart00209    5 SEWSPCSVTCGGGVQTRTRSCCSP-----PPQNGGGPC---TGEDVETRACNEQPC 52

sporozoite surface protein 2 (SSP2); Provisional

                           10        20
                   ....*....|....*....|...
gi 1476587899   30 GPWSQWSPCSRTCGGGVSFRERP 52
Cdd:PTZ00441   241 GPWDEWTPCSVTCGKGTHSRSRP 263

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 1476587899  798 PQPGASGRSTHTDGGGSSPAGEQEPSQHRTGAAVQRKPWPSGGLWRQDQQPGPGEAPHTQAFGEWPWGQELGSRAPGLGG 877
Cdd:pfam16626    1 PEPGASGQSTHTDGGGSGPGGQQEASWHRTGATVQRKPLPSGGLWRRDQEPGPGEAPHTQAFGERPWGQELGPRAPGLGG 80

                           90
                   ....*....|..
gi 1476587899  878 DAGSPAPPFHSS 889
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
                   ....*....|....*....|....*....|....*....|
gi 1476587899  749 DWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 788
Cdd:cd22635     13 DYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1476587899 1031 QNQPRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQPVSSPRHQLQPD----GSLVISRVAVEDGGFYTCVAFN 1100
Cdd:pfam13927    5 TVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPISSGSTRSRSLsgsnSTLTISNVTRSDAGTYTCVASN 78

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1476587899  1034 PRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQ--PVSSPRHQLQPDG---SLVISRVAVEDGGFYTCVAFNGQDRDQRW 1108
Cdd:smart00410    1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGklLAESGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSSGSASSG 80

                    ....*
gi 1476587899  1109 VQLRV 1113
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 1476587899  366 WKAGPWAPCSASCGGGSQSRSVYCISSDGagiQEAVEEAECAGLPgKPPAIQACNLQRC 424
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGG---GSIVPDSECSAQK-KPPETQSCNLKPC 55

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

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1476587899  753 RWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 788
Cdd:cd00109     16 RWYYNSETGQCEEFIYGGCGGNANNFETKEECEATC 51

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1476587899  308 WSHGSWSDCSAECGGGHQSRLVFCTI--DHEAYPDHMCQRQPRPADRRSCNLHPC 360
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQkgGGSIVPDSECSAQKKPPETQSCNLKPC 55

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.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1476587899 1045 IRMTCRAEGFPPPAIEWQRDGQPVSS----PRHQLQPDGSLVISRVAVEDGGFYTCVAFNG 1101
Cdd:cd00096      1 VTLTCSASGNPPPTITWYKNGKPLPPssrdSRRSELGNGTLTISNVTLEDSGTYTCVASNS 61

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 1476587899   85 DFRAEQCAEFDGAEFQGRR-----YRW---LPYYSAPNKCELNCIPKGENFYYKHREAVVDGTPCEP------GKRDVCV 150
Cdd:pfam19236    4 EFMSQQCARTDGQPLRSSPggasfYHWgaaVPHSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPsgpredGTLSLCV 83

                           90       100       110
                   ....*....|....*....|....*....|..
gi 1476587899  151 DGSCRVVGCDHELDSSKQEDKCLRCGGDGTTC 182
Cdd:pfam19236   84 LGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

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 1476587899 1123 PPTV------TVPEGDTARLLCVVAGESV-NIRWSRNG--LPVqadGHRVHQSPDGTLLIYNL-RARDEGSYTCSAY-QG 1191
Cdd:cd20958      1 PPFIrpmgnlTAVAGQTLRLHCPVAGYPIsSITWEKDGrrLPL---NHRQRVFPNGTLVIENVqRSSDEGEYTCTARnQQ 77

                           90
                   ....*....|..
gi 1476587899 1192 SQAVSRSTEVKV 1203
Cdd:cd20958     78 GQSASRSVFVKV 89

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
                   ....*....|....*....|....*....|....*...
gi 1476587899  753 RWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSCQG 790
Cdd:cd22624     17 RWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETCSG 54

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.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1476587899 1031 QNQPRVVDASPGQRIRMTCRAEGFPPPAIEWQRDGQPVSSPRHQLQ-PDGSLVISRVAVEDGGFYTCVAFN 1100
Cdd:cd20978      5 QKPEKNVVVKGGQDVTLPCQVTGVPQPKITWLHNGKPLQGPMERATvEDGTLTIINVQPEDTGYYGCVATN 75

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 1476587899  898 VEPSLVQAALGQLVRLSCSDDTA-PESQAAWQKDGQPISSD--RHRLQFDGSLIIHPLQAEDAGTYSC 962
Cdd:cd05724      2 VEPSDTQVAVGEMAVLECSPPRGhPEPTVSWRKDGQPLNLDneRVRIVDDGNLLIAEARKSDEGTYKC 69

Fourth 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 fourth 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 1476587899 1040 SPGQRIRMTCRAEGFPPPAIEWQRDGQPVS-SPRHQL----QPDGSLV----ISRVAVEDGGFYTCVAFNG 1101
Cdd:cd20956     14 QPGPSVSLKCVASGNPLPQITWTLDGFPIPeSPRFRVgdyvTSDGDVVsyvnISSVRVEDGGEYTCTATND 84

Immunoglobulin I-set domain of the Leucine-rich repeat and immunoglobin-like domain-containing protein 1 (Lingo-1); The members here are composed of the immunoglobulin I-set (IgI) domain of the Leucine-rich repeat and immunoglobin-like domain-containing protein 1 (Lingo-1). Human Lingo-1 is a central nervous system-specific transmembrane glycoprotein also known as LERN-1, which functions as a negative regulator of neuronal survival, axonal regeneration, and oligodendrocyte differentiation and myelination. Lingo-1 is a key component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors. The ligand-binding ectodomain of human Lingo-1 contains a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. Diseases associated with Lingo-1 include mental retardation, autosomal recessive 64 and essential tremor. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. 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. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the Lingo-1 lacks this strand and thus it belongs to the I-set of the IgSF. 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 hemolymph protein hemolin, 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 1476587899 1026 RLRLDQNQPRVVDAspGQRIRMTCRAEGFPPPAIEW-QRDGQPVSSP---RHQLQPDGSLVISRVAVEDGGFYTCVAFNG 1101
Cdd:cd20969      3 AIRDRKAQQVFVDE--GHTVQFVCRADGDPPPAILWlSPRKHLVSAKsngRLTVFPDGTLEVRYAQVQDNGTYLCIAANA 80

                           90
                   ....*....|..
gi 1476587899 1102 QDRDQRWVQLRV 1113
Cdd:cd20969     81 GGNDSMPAHLHV 92

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.

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                   ....*....|....*....|....*....|....*....|...
gi 1476587899  746 PSHDWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 788
Cdd:cd22628      9 PCREYVVKWYYDKQANSCAQFWYGGCEGNRNRFETEEECRKTC 51

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

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                   ....*....|....*....|....*....|....*....|
gi 1476587899  749 DWAARWYFVASVGQCNRFWYGGCHGNANNFASEQECMSSC 788
Cdd:cd22629     14 DFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53