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 564329185   141 DFRAQQCSAYNDVQYQ-----GHYYEW---IPlHNDPAAPCALKCHARGQSLVVELAPKVLDGTRCNAD------TLDMC 206
Cdd:pfam19236    4 EFMSQQCARTDGQPLRsspggASFYHWgaaVP-HSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPSgpredgTLSLC 82

                           90       100       110
                   ....*....|....*....|....*....|...
gi 564329185   207 ISGICQTVGCDRQLGSSAKKDNCGVCAGDGSTC 239
Cdd:pfam19236   83 VLGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 564329185  1500 WFTSMWSECSVSCGGGSHSRQVMCKQTKANGtvqVVSPRACASKDRPLGRKPCSVRPC 1557
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGS---IVPDSECSAQKKPPETQSCNLKPC 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 564329185  942 SVIIKCPVRHFQKSLIQWEKDGHCLKNSKQLGITKSGSLKIHSLSTPDIGVYRCIA----GSAQETVVL 1006
Cdd:cd04969    19 DVIIECKPKASPKPTISWSKGTELLTNSSRICILPDGSLKIKNVTKSDEGKYTCFAvnffGKANSTGSL 87

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 564329185  1441 WEPGNWTHCSATCGPlGVRLQRPQCMMASGQE-VSEALCGPHRKPLAgFQSCNIRDC 1496
Cdd:pfam19030    1 WVAGPWGECSVTCGG-GVQTRLVQCVQKGGGSiVPDSECSAQKKPPE-TQSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   661 WEYAGFTPCTATCLGGYQEAIAVCLHIQTHQTVNDSLCDLAHRPPPMsQACHTEPC 716
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPDSECSAQKKPPET-QSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   494 WIAMEWSQCTVTCGRGLRYRVVLCINHRGQHVGG---CNPQMKLHIKEECVIPvPC 546
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPdseCSAQKKPPETQSCNLK-PC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   838 AGDWSKCSVTCGVGFQRRKQVCQKltaKGRRVPLAETLCRDLPGLPLVRPCQMPVC 893
Cdd:pfam19030    3 AGPWGECSVTCGGGVQTRLVQCVQ---KGGGSIVPDSECSAQKKPPETQSCNLKPC 55

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564329185  1197 PPSVS-FNKTINARIGNTVYITkstevinilCSlVTPSSEATYTWTKDGALLQP---SVKIIVDETGKMQIQNPTRKEQG 1272
Cdd:pfam13927    1 KPVITvSPSSVTVREGETVTLT---------CE-ATGSPPPTITWYKNGEPISSgstRSRSLSGSNSTLTISNVTRSDAG 70

                   ....*.
gi 564329185  1273 IYECSV 1278
Cdd:pfam13927   71 TYTCVA 76

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 564329185   141 DFRAQQCSAYNDVQYQ-----GHYYEW---IPlHNDPAAPCALKCHARGQSLVVELAPKVLDGTRCNAD------TLDMC 206
Cdd:pfam19236    4 EFMSQQCARTDGQPLRsspggASFYHWgaaVP-HSQGDALCRHMCRAIGESFIMKRGDSFLDGTRCMPSgpredgTLSLC 82

                           90       100       110
                   ....*....|....*....|....*....|...
gi 564329185   207 ISGICQTVGCDRQLGSSAKKDNCGVCAGDGSTC 239
Cdd:pfam19236   83 VLGSCRTFGCDGRMDSQQVWDRCQVCGGDNSTC 115

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564329185   1313 HLSVVVGGiveaalqaNVTIHCPVKGVPQPNVTWLKRGGSL---SDNVSLLFNG---SLLLQNASLENEGTYICTATNAL 1386
Cdd:smart00410    3 SVTVKEGE--------SVTLSCEASGSPPPEVTWYKQGGKLlaeSGRFSVSRSGstsTLTISNVTPEDSGTYTCAATNSS 74

                    ....*.
gi 564329185   1387 GKAVAT 1392
Cdd:smart00410   75 GSASSG 80

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 564329185  1500 WFTSMWSECSVSCGGGSHSRQVMCKQTKANGtvqVVSPRACASKDRPLGRKPCSVRPC 1557
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGS---IVPDSECSAQKKPPETQSCNLKPC 55

Fifth immunoglobulin (Ig) domain of contactin; The members here are composed of the fifth immunoglobulin (Ig) domain of contactins. Contactins are neural cell adhesion molecules and are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module via contacts between Ig domains 1 and 4, and between Ig domains 2 and 3. Contactin-2 (TAG-1, axonin-1) may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. This group also includes contactin-1 and contactin-5. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-5 is expressed specifically in the rat postnatal nervous system, peaking at about 3 weeks postnatal, and a lack of contactin-5 (NB-2) results in an impairment of neuronal activity in the rat auditory system. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala. Contactin-1 is differentially expressed in tumor tissues and may, through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 564329185  942 SVIIKCPVRHFQKSLIQWEKDGHCLKNSKQLGITKSGSLKIHSLSTPDIGVYRCIA----GSAQETVVL 1006
Cdd:cd04969    19 DVIIECKPKASPKPTISWSKGTELLTNSSRICILPDGSLKIKNVTKSDEGKYTCFAvnffGKANSTGSL 87

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 564329185  1441 WEPGNWTHCSATCGPlGVRLQRPQCMMASGQE-VSEALCGPHRKPLAgFQSCNIRDC 1496
Cdd:pfam19030    1 WVAGPWGECSVTCGG-GVQTRLVQCVQKGGGSiVPDSECSAQKKPPE-TQSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   661 WEYAGFTPCTATCLGGYQEAIAVCLHIQTHQTVNDSLCDLAHRPPPMsQACHTEPC 716
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPDSECSAQKKPPET-QSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   494 WIAMEWSQCTVTCGRGLRYRVVLCINHRGQHVGG---CNPQMKLHIKEECVIPvPC 546
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPdseCSAQKKPPETQSCNLK-PC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   838 AGDWSKCSVTCGVGFQRRKQVCQKltaKGRRVPLAETLCRDLPGLPLVRPCQMPVC 893
Cdd:pfam19030    3 AGPWGECSVTCGGGVQTRLVQCVQ---KGGGSIVPDSECSAQKKPPETQSCNLKPC 55

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 564329185   933 SRAYLLLNTSVIIKCPVRHFQKSLIQWEKDGHCLKNSKQLGIT---KSGSLKIHSLSTPDIGVYRCIA 997
Cdd:pfam13927    9 SSVTVREGETVTLTCEATGSPPPTITWYKNGEPISSGSTRSRSlsgSNSTLTISNVTRSDAGTYTCVA 76

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

                            10        20        30
                    ....*....|....*....|....*....|
gi 564329185    498 EWSQCTVTCGRGLRYRVVLCINHRGQHVGG 527
Cdd:smart00209    6 EWSPCSVTCGGGVQTRTRSCCSPPPQNGGG 35

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 564329185 1223 INILCSlVTPSSEATYTWTKDGALLQPSVK---IIVDETGKMQIQNPTRKEQGIYECSVASHQGSDVESSL 1290
Cdd:cd00096     1 VTLTCS-ASGNPPPTITWYKNGKPLPPSSRdsrRSELGNGTLTISNVTLEDSGTYTCVASNSAGGSASASV 70

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

                            10        20
                    ....*....|....*....|.
gi 564329185    438 PWTACSVSCGGGIQRRSFVCV 458
Cdd:smart00209    6 EWSPCSVTCGGGVQTRTRSCC 26

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

                            10        20
                    ....*....|....*....|.
gi 564329185    583 EPWSACSTTCGPGIQVREVRC 603
Cdd:smart00209    5 SEWSPCSVTCGGGVQTRTRSC 25

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

                            10        20
                    ....*....|....*....|....
gi 564329185   1500 WFTSMWSECSVSCGGGSHSRQVMC 1523
Cdd:smart00209    2 SEWSEWSPCSVTCGGGVQTRTRSC 25

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 564329185 1330 VTIHCPVKGVPQPNVTWLKRGGSLSDNV--SLLFNGSLLLQNASLENEGTYICTATNALGK 1388
Cdd:cd20978    19 VTLPCQVTGVPQPKITWLHNGKPLQGPMerATVEDGTLTIINVQPEDTGYYGCVATNEIGD 79

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 564329185  1322 VEAALQANVTIHCPVKGVPQPNVTWLKRGGSL--SDNVSLLFNG---SLLLQNASLENEGTYICTATNALGKAVATSGL 1395
Cdd:pfam07679   10 VEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrsSDRFKVTYEGgtyTLTISNVQPDDSGKYTCVATNSAGEAEASAEL 88

Fifth immunoglobulin (Ig) domain of contactin; The members here are composed of the fifth immunoglobulin (Ig) domain of contactins. Contactins are neural cell adhesion molecules and are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module via contacts between Ig domains 1 and 4, and between Ig domains 2 and 3. Contactin-2 (TAG-1, axonin-1) may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. This group also includes contactin-1 and contactin-5. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-5 is expressed specifically in the rat postnatal nervous system, peaking at about 3 weeks postnatal, and a lack of contactin-5 (NB-2) results in an impairment of neuronal activity in the rat auditory system. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala. Contactin-1 is differentially expressed in tumor tissues and may, through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 564329185 1324 AALQANVTIHCPVKGVPQPNVTWLKRGGSL--SDNVSLLFNGSLLLQNASLENEGTYICTATNALGKAVATSGL 1395
Cdd:cd04969    14 AAKGGDVIIECKPKASPKPTISWSKGTELLtnSSRICILPDGSLKIKNVTKSDEGKYTCFAVNFFGKANSTGSL 87

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 564329185   434 WEHNPWTACSVSCGGGIQRRSFVCVEEsmHAEILQVEEWkCMYAPKPKVMQTCNLFDC 491
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQK--GGGSIVPDSE-CSAQKKPPETQSCNLKPC 55

Third 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 third 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 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, 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, and 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 Slit2 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 564329185 1330 VTIHCPVKGVPQPNVTWLKRGGSLSDN-VSLLFNGSLLLQNASLENEGTYICTATNALGKAVATSGLR 1396
Cdd:cd05725    15 AEFQCEVGGDPVPTVRWRKEDGELPKGrYEILDDHSLKIRKVTAGDMGSYTCVAENMVGKIEASATLT 82

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 564329185   720 WHMGSWGACSATCGVGIQTRDVYCVHPE-ESPAPPEECRD-EKPHALRACNQFDC 772
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGgGSIVPDSECSAqKKPPETQSCNLKPC 55

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 564329185  1616 WRVGPWKPCTAVCGRGFQSRKVNCIHTGSCKPMADRYC-VQMKPASWRHCFGPSC 1669
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPDSECsAQKKPPETQSCNLKPC 55

Fifth Ig-like domain of Roundabout (Robo) homolog 1/2, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth Ig-like domain of Roundabout (Robo) homolog 1/2 and similar domains. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of 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, -2, and -3), and three mammalian Slit homologs (Slit-1,-2, -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, -2, and -3 are expressed by commissural neurons in the vertebrate spinal cord and Slits 1, -2, -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 Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. The fifth Ig-like domain of Robo 1 and 2 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. 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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564329185 1316 VVVGGiveaalqaNVTIHCPVKGVPQPNVTWLKRGGSLS---DNVSLLFNGSLLLQNASLENEGTYICTATNALGKAVAT 1392
Cdd:cd20952    11 VAVGG--------TVVLNCQATGEPVPTISWLKDGVPLLgkdERITTLENGSLQIKGAEKSDTGEYTCVALNLSGEATWS 82

                  ...
gi 564329185 1393 SGL 1395
Cdd:cd20952    83 AVL 85

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 564329185     90 WDAWGDWSDCSRTCGGGASYSLRRCLT------GRNCEGQNIRYKTCSNHDCP 136
Cdd:smart00209    1 WSEWSEWSPCSVTCGGGVQTRTRSCCSpppqngGGPCTGEDVETRACNEQPCP 53

agrin-responsive first immunoglobulin-like domains (Ig1) of the MuSK ectodomain; a member of the I-set of IgSF domains; The members here are composed of the first immunoglobulin-like domains (Ig1) of the Muscle-specific kinase (MuSK). MuSK is a receptor tyrosine kinase specifically expressed in skeletal muscle, where it plays a central role in the formation and maintenance of the neuromuscular junction (NMJ). MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. 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 MuSK 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564329185 1328 ANVTIHCPVKGVPQPNVTWLKRGGS---LSDNVSLLFNGSLL-LQNASLENEGTYICTATNALGKAV 1390
Cdd:cd20970    18 ENATFMCRAEGSPEPEISWTRNGNLiieFNTRYIVRENGTTLtIRNIRRSDMGIYLCIASNGVPGSV 84

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 564329185 1314 LSVVVGgiveaalqANVTIHCPVKGVPQPNVTWLKRGGSLSDN--VSLLFNGSLLLQNASL-ENEGTYICTATN 1384
Cdd:cd20958    10 LTAVAG--------QTLRLHCPVAGYPISSITWEKDGRRLPLNhrQRVFPNGTLVIENVQRsSDEGEYTCTARN 75

Immunoglobulin domain; Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 564329185  1329 NVTIHCPVK-GVPQPNVTWLKRGGSL------SDNVSLLFNGSLLLQNASLENEGTYICTATNALGKAVATS 1393
Cdd:pfam00047   13 SATLTCSAStGSPGPDVTWSKEGGTLieslkvKHDNGRTTQSSLLISNVTKEDAGTYTCVVNNPGGSATLST 84

Third immunoglobulin (Ig) domain of contactin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig) domain of contactins. Contactins are neural cell adhesion molecules and are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module via contacts between Ig domains 1 and 4, and between Ig domains 2 and 3. Contactin-2 (TAG-1, axonin-1) may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. This group also includes contactin-1 and contactin-5. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-5 is expressed specifically in the rat postnatal nervous system, peaking at about 3 weeks postnatal, and a lack of contactin-5 (NB-2) results in an impairment of neuronal activity in the rat auditory system. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala. Contactin-1 is differentially expressed in tumor tissues and may, through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma. This group belongs to the I-set of IgSF domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 564329185 1322 VEAALQANVTIHCPVKGVPQPNVTWLKRGGSL-SDNVSLLFNGSLLLQNASLENEGTYICTATNALGK 1388
Cdd:cd04968    11 TYALKGQTVTLECFALGNPVPQIKWRKVDGSPsSQWEITTSEPVLEIPNVQFEDEGTYECEAENSRGK 78

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

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                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 564329185   494 WIAMEWSQCTVTCGRGLRYRVVLCINHRGQHVGG---CNPQMKLHIKEECVIPvPC 546
Cdd:pfam19030    1 WVAGPWGECSVTCGGGVQTRLVQCVQKGGGSIVPdseCSAQKKPPETQSCNLK-PC 55

Second immunoglobulin (Ig)-like domain of the receptor protein tyrosine phosphatase (RPTP)-F; member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain found in the receptor protein tyrosine phosphatase (RPTP)-F, also known as LAR. LAR belongs to the RPTP type IIa subfamily. Members of this subfamily are cell adhesion molecule-like proteins involved in central nervous system (CNS) development. They have large extracellular portions comprised of multiple Ig-like domains and two to nine fibronectin type III (FNIII) domains and a cytoplasmic portion having two tandem phosphatase domains.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 564329185 1321 IVEAALQAnvTIHCPVKGVPQPNVTWLKR-----GGSLSDNVSLLFNGSLLLQNASLENEGTYICTATNALG 1387
Cdd:cd05738    10 VVEKARTA--TMLCAASGNPDPEISWFKDflpvdTATSNGRIKQLRSGALQIENSEESDQGKYECVATNSAG 79

First immunoglobulin (Ig)-like domain in neogenin, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the first immunoglobulin (Ig)-like domain in neogenin and related proteins. Neogenin is a cell surface protein which is expressed in the developing nervous system of vertebrate embryos in the growing nerve cells. It is also expressed in other embryonic tissues and may play a general role in developmental processes such as cell migration, cell-cell recognition, and tissue growth regulation. Included in this group is the tumor suppressor protein DCC which is deleted in colorectal carcinoma. DCC and neogenin each have four Ig-like domains followed by six fibronectin type III domains, a transmembrane domain, and an intracellular domain. 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564329185 1327 QANVTIHCPVKGVPQPNVTWLKRGGSLS----DNVSLLFNGSLLLQN-----ASLENEGTYICTATN 1384
Cdd:cd05722    16 GGPVVLNCSAESDPPPKIEWKKDGVLLNlvsdERRQQLPNGSLLITSvvhskHNKPDEGFYQCVAQN 82