UPA domain; The UPA domain is conserved in UNC5, PIDD, and Ankyrins. It has a beta sandwich structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 682 AVKQLKVAVFGCMSCNSLDYNLRVYCVDNTPCAFQEVVSDERHQGGQLLEEPKLLHFKGNTFSLQISVLDIPPFLWRIKP 761
Cdd:pfam17217   1 AIKRLRLAVFAPAACTSLEYSLRVYCLDDTPDALKEVVQLEKQLGGQLLEEPKTLHFKDSTHNLRLSIHDIPPSLWKSKL 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 762 FTACQEVPFSRVWCSNRQPLHCAFSLERYTPTTTQLSCKICIRQLKGHEQILQVQTSILE 821
Cdd:pfam17217  81 FAKYQEIPFYHVWSGNQNPLHCTFTLERYSLATTELSCKICVRQVEGEGQIFQLYTTLAE 140

ZU5 domain; Domain present in ZO-1 and Unc5-like netrin receptors Domain of unknown function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 539 TTGVFGHLGGRLVMPNTGVSLLIPHGAIPEENSWEIYMSINQGEPSL-QSDGSEVLLSPEVTCGPPDMIVTTPFALTIPH 617
Cdd:pfam00791   1 VSGLVDSRGGRLVLPNSGVSLLIPPGAIPEGTRIECYLAVNRDESSRpPLEEGETLLSPVVECGPPGLKFLKPVILEVPH 80

                          90
                  ....*....|....*..
gi 1018191617 618 CADVSSEHWNIHLKKRT 634
Cdd:pfam00791  81 CASLRPEEWEIVLKRSD 97

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1018191617  250 WSSWTEWSACNVRCGRGWQKRSRTCTNPAPLNGGAFCEGMSVQKITC-TSLCP 301
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACnEQPCP 53

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617  49 PHFIEEPDDAYIIKSNPIALRCKA--RPAMQIFFKCNGEWV--HQNEHVSEETLDESSGLKVREVFINVTRQQVEDFhgp 124
Cdd:cd07693     1 PRIVEHPSDLIVSKGDPATLNCKAegRPTPTIQWLKNGQPLetDKDDPRSHRIVLPSGSLFFLRVVHGRKGRSDEGV--- 77

                          90       100
                  ....*....|....*....|....*.
gi 1018191617 125 edYWCqcVAWSHLGTSKSRKASVRIA 150
Cdd:cd07693    78 --YVC--VAHNSLGEAVSRNASLEVA 99

UPA domain; The UPA domain is conserved in UNC5, PIDD, and Ankyrins. It has a beta sandwich structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 682 AVKQLKVAVFGCMSCNSLDYNLRVYCVDNTPCAFQEVVSDERHQGGQLLEEPKLLHFKGNTFSLQISVLDIPPFLWRIKP 761
Cdd:pfam17217   1 AIKRLRLAVFAPAACTSLEYSLRVYCLDDTPDALKEVVQLEKQLGGQLLEEPKTLHFKDSTHNLRLSIHDIPPSLWKSKL 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 762 FTACQEVPFSRVWCSNRQPLHCAFSLERYTPTTTQLSCKICIRQLKGHEQILQVQTSILE 821
Cdd:pfam17217  81 FAKYQEIPFYHVWSGNQNPLHCTFTLERYSLATTELSCKICVRQVEGEGQIFQLYTTLAE 140

ZU5 domain; Domain present in ZO-1 and Unc5-like netrin receptors Domain of unknown function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 539 TTGVFGHLGGRLVMPNTGVSLLIPHGAIPEENSWEIYMSINQGEPSL-QSDGSEVLLSPEVTCGPPDMIVTTPFALTIPH 617
Cdd:pfam00791   1 VSGLVDSRGGRLVLPNSGVSLLIPPGAIPEGTRIECYLAVNRDESSRpPLEEGETLLSPVVECGPPGLKFLKPVILEVPH 80

                          90
                  ....*....|....*..
gi 1018191617 618 CADVSSEHWNIHLKKRT 634
Cdd:pfam00791  81 CASLRPEEWEIVLKRSD 97

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 158 QDPQGREVPIEGMIVLHCRPPEGVPAAEVEWLKNEEPIDsEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIVAKRRS 237
Cdd:cd05724     2 VEPSDTQVAVGEMAVLECSPPRGHPEPTVSWRKDGQPLN-LDNERVRIVDDGNLLIAEARKSDEGTYKCVATNMVGERES 80

                  ....*..
gi 1018191617 238 LSATVVV 244
Cdd:cd05724    81 RAARLSV 87

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1018191617  250 WSSWTEWSACNVRCGRGWQKRSRTCTNPAPLNGGAFCEGMSVQKITC-TSLCP 301
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACnEQPCP 53

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1018191617  306 WEVWSEWSVCSPECEH---LRIRECTAPPPRNGGKFCEGLSQESENCTDGLC 354
Cdd:smart00209   1 WSEWSEWSPCSVTCGGgvqTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPC 52

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1018191617  852 IRQRICATFDTPnaKGKDWQMLAQKNSINRN-LSYFATQS-----SPSAVILNLWEARHQHDGDLDSLACALEEIGRTH 924
Cdd:smart00005   4 TRQKLAKLLDHP--LGLDWRELARKLGLSEAdIDQIRTEAprdlaEQSVQLLRLWEQREGKNATLGTLLEALRKMGRDD 80

Thrombospondin type 1 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1018191617 308 VWSEWSVCSPECE---HLRIRECTAPPPrnGGKFCEGLSQESENCTDGLC 354
Cdd:pfam00090   2 PWSPWSPCSVTCGkgiQVRQRTCKSPFP--GGEPCTGDDIETQACKMDKC 49

UPA domain; The UPA domain is conserved in UNC5, PIDD, and Ankyrins. It has a beta sandwich structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 682 AVKQLKVAVFGCMSCNSLDYNLRVYCVDNTPCAFQEVVSDERHQGGQLLEEPKLLHFKGNTFSLQISVLDIPPFLWRIKP 761
Cdd:pfam17217   1 AIKRLRLAVFAPAACTSLEYSLRVYCLDDTPDALKEVVQLEKQLGGQLLEEPKTLHFKDSTHNLRLSIHDIPPSLWKSKL 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 762 FTACQEVPFSRVWCSNRQPLHCAFSLERYTPTTTQLSCKICIRQLKGHEQILQVQTSILE 821
Cdd:pfam17217  81 FAKYQEIPFYHVWSGNQNPLHCTFTLERYSLATTELSCKICVRQVEGEGQIFQLYTTLAE 140

ZU5 domain; Domain present in ZO-1 and Unc5-like netrin receptors Domain of unknown function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 539 TTGVFGHLGGRLVMPNTGVSLLIPHGAIPEENSWEIYMSINQGEPSL-QSDGSEVLLSPEVTCGPPDMIVTTPFALTIPH 617
Cdd:pfam00791   1 VSGLVDSRGGRLVLPNSGVSLLIPPGAIPEGTRIECYLAVNRDESSRpPLEEGETLLSPVVECGPPGLKFLKPVILEVPH 80

                          90
                  ....*....|....*..
gi 1018191617 618 CADVSSEHWNIHLKKRT 634
Cdd:pfam00791  81 CASLRPEEWEIVLKRSD 97

Death domain found in Uncoordinated-5B; Death Domain (DD) found in Uncoordinated-5B (UNC5B). UNC5B is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis. UNC5B signaling is involved in the netrin-1-induced proliferation and migration of renal proximal tubular cells. It is also required for vascular patterning during embryonic development, and its activation inhibits sprouting angiogenesis. UNC5 proteins are transmembrane proteins with an extracellular domain consisting of two immunoglobulin repeats, two thrombospondin type-I modules and an intracellular region containing a ZU-5 domain, UPA domain and a DD. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1018191617 848 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRT 923
Cdd:cd08802     1 IPLSIRQKICNSLDAPNSRGNDWRLLAQKLSMDRYLNYFATKASPTGVILDLWEARHQDDGDLNSLASALEEMGKS 76

Death domain found in Uncoordinated-5A; Death Domain (DD) found in Uncoordinated-5A (UNC5A). UNC5A is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a critical role in neuronal development and differentiation, as well as axon-guidance. It also plays a role in regulating apoptosis in non-neuronal cells as a downstream target of p53. UNC5 proteins are transmembrane proteins with an extracellular domain consisting of two immunoglobulin repeats, two thrombospondin type-I modules and an intracellular region containing a ZU-5 domain, UPA domain and a DD. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 848 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTKL 927
Cdd:cd08800     1 IPFLIRQKIISSLDPPCPRGADWRTLAQKLNLDSHLSFFASKSSPTAMILNLWEAQHFPNGNLSQLAAVVAEIGKQDAML 80

                  ....
gi 1018191617 928 SNIS 931
Cdd:cd08800    81 FLVS 84

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 158 QDPQGREVPIEGMIVLHCRPPEGVPAAEVEWLKNEEPIDsEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIVAKRRS 237
Cdd:cd05724     2 VEPSDTQVAVGEMAVLECSPPRGHPEPTVSWRKDGQPLN-LDNERVRIVDDGNLLIAEARKSDEGTYKCVATNMVGERES 80

                  ....*..
gi 1018191617 238 LSATVVV 244
Cdd:cd05724    81 RAARLSV 87

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1018191617  250 WSSWTEWSACNVRCGRGWQKRSRTCTNPAPLNGGAFCEGMSVQKITC-TSLCP 301
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACnEQPCP 53

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 156 FEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENIDTRAD-HNLIIRQARLSDSGNYTCMAANIVAK 234
Cdd:pfam07679   3 FTQKPKDVEVQEGESARFTCTV-TGTPDPEVSWFKDGQPLRSSDRFKVTYEGGtYTLTISNVQPDDSGKYTCVATNSAGE 81

                          90
                  ....*....|
gi 1018191617 235 RRSlSATVVV 244
Cdd:pfam07679  82 AEA-SAELTV 90

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 1018191617 156 FEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIdSEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIVAKr 235
Cdd:cd20952     2 ILQGPQNQTVAVGGTVVLNCQA-TGEPVPTISWLKDGVPL-LGKDERITTLENGSLQIKGAEKSDTGEYTCVALNLSGE- 78

                  ....*....
gi 1018191617 236 RSLSATVVV 244
Cdd:cd20952    79 ATWSAVLDV 87

Immunoglobulin (Ig)-like domain in neuregulins; The members here are composed of the immunoglobulin (Ig)-like domain in neuregulins (NRGs). NRGs are signaling molecules which participate in cell-cell interactions in the nervous system, breast, heart, and other organ systems, and are implicated in the pathology of diseases including schizophrenia, multiple sclerosis, and breast cancer. There are four members of the neuregulin gene family (NRG-1, NRG-2, NRG-3, and NRG-4). The NRG-1 protein, binds to and activates the tyrosine kinases receptors ErbB3 and ErbB4, initiating signaling cascades. The other NRGs proteins bind one or the other or both of these ErbBs. NRG-1 has multiple functions: in the brain it regulates various processes such as radial glia formation and neuronal migration, dendritic development, and expression of neurotransmitters receptors, while in the peripheral nervous system NRG-1 regulates processes such as target cell differentiation, and Schwann cell survival. There are many NRG-1 isoforms which arise from the alternative splicing of mRNA. Less is known of the functions of the other NRGs. NRG-2 and NRG-3 are expressed predominantly in the nervous system. NRG-2 is expressed by motor neurons and terminal Schwann cells, and is concentrated near synaptic sites and may be a signal that regulates synaptic differentiation. NRG-4 has been shown to direct pancreatic islet cell development towards the delta-cell lineage.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1018191617 171 IVLHCRPPEGVPAAEVEWLKNEEPIDSEQDENI---DTRADHNLIIRQARLSDSGNYTCMAANIVAKRrslSATVVVYV 246
Cdd:cd05750    17 LVLKCEATSENPSPRYRWFKDGKELNRKRPKNIkirNKKKNSELQINKAKLEDSGEYTCVVENILGKD---TVTGNVTV 92

Second Ig-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins. Titin is a key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. 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 titin Z1z2 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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 155 NFEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENIDTRAD-HNLIIRQARLSDSGNYTCMAANIVA 233
Cdd:cd20972     3 QFIQKLRSQEVAEGSKVRLECRV-TGNPTPVVRWFCEGKELQNSPDIQIHQEGDlHSLIIAEAFEEDTGRYSCLATNSVG 81

                          90
                  ....*....|.
gi 1018191617 234 kRRSLSATVVV 244
Cdd:cd20972    82 -SDTTSAEIFV 91

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617 155 NFEQDPQGREVPIE--GMIVLHCRPpEGVPAAEVEWLKNEEPIdsEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIV 232
Cdd:cd04969     2 DFELNPVKKKILAAkgGDVIIECKP-KASPKPTISWSKGTELL--TNSSRICILPDGSLKIKNVTKSDEGKYTCFAVNFF 78

                          90
                  ....*....|..
gi 1018191617 233 AKRRSlSATVVV 244
Cdd:cd04969    79 GKANS-TGSLSV 89

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1018191617  160 PQGREVPIEGMIVLHCRPPeGVPAAEVEWLKN-EEPIDSEQDENIDTRA-DHNLIIRQARLSDSGNYTCMAANivaKRRS 237
Cdd:smart00410   1 PPSVTVKEGESVTLSCEAS-GSPPPEVTWYKQgGKLLAESGRFSVSRSGsTSTLTISNVTPEDSGTYTCAATN---SSGS 76

                   ....*....
gi 1018191617  238 LSATVVVYV 246
Cdd:smart00410  77 ASSGTTLTV 85

Immunoglobulin (Ig)-like domain of titin and similar proteins; The members here are composed of the immunoglobulin (Ig)-like domain found in titin-like proteins and similar proteins. Titin (also called connectin) is a fibrous sarcomeric protein specifically found in vertebrate striated muscle. Titin is a giant protein; 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. It appears to function similarly to an elastic band, keeping the myosin filaments centered in the sarcomere during muscle contraction or stretching. Within the sarcomere, titin is also attached to or is associated with myosin binding protein C (MyBP-C). MyBP-C appears to contribute to the generation of passive tension by titin and like titin has repeated Ig-like and FN-III domains. Also included in this group are worm twitchin and insect projectin, thick filament proteins of invertebrate muscle which also have repeated Ig-like and FN-III domains.

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gi 1018191617 180 GVPAAEVEWLKNEEPIDSEQDENIDTRADHN-LIIRQARLSDSGNYTCMAANIVAKRrslSATVVVYV 246
Cdd:cd05748    18 GRPTPTVTWSKDGQPLKETGRVQIETTASSTsLVIKNAKRSDSGKYTLTLKNSAGEK---SATINVKV 82

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 1018191617 158 QDPQGREVPIEGMIVLHCRPPEGVPAAEVEWLK-NEEPIDSEQD-ENIDTRADHNLIIRQARLSDSGNYTCMAAN 230
Cdd:pfam00047   1 SAPPTVTVLEGDSATLTCSASTGSPGPDVTWSKeGGTLIESLKVkHDNGRTTQSSLLISNVTKEDAGTYTCVVNN 75

Third immunoglobulin (Ig)-like domain of Neural Cell Adhesion Molecule 1 (NCAM-1); member of the I-set of IgSF domains; The members here are composed of the third immunoglobulin (Ig)-like domain of Neural Cell Adhesion Molecule (NCAM-1). NCAM plays important roles in the development and regeneration of the central nervous system, in synaptogenesis and neural migration. NCAM mediates cell-cell and cell-substratum recognition and adhesion via homophilic (NCAM-NCAM), and heterophilic (NCAM-non-NCAM), interactions. NCAM is expressed as three major isoforms having different intracellular extensions. The extracellular portion of NCAM has five N-terminal Ig-like domains and two fibronectin type III domains. The double zipper adhesion complex model for NCAM homophilic binding involves Ig1, Ig2, and Ig3. By this model, Ig1 and Ig2 mediate dimerization of NCAM molecules situated on the same cell surface (cis interactions), and Ig3 domains mediate interactions between NCAM molecules expressed on the surface of opposing cells (trans interactions) through binding to the Ig1 and Ig2 domains. The adhesive ability of NCAM is modulated by the addition of polysialic acid chains to the fifth Ig-like domain.

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gi 1018191617 171 IVLHCrPPEGVPAAEVEWLKNEEPIDSEQDENIDTRADHNLIIRQARLSDSGNYTCMAAN 230
Cdd:cd05730    21 VTLAC-DADGFPEPTMTWTKDGEPIESGEEKYSFNEDGSEMTILDVDKLDEAEYTCIAEN 79

Sixth immunoglobulin (Ig) domain of contactin; The members here are composed of the sixth 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.

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gi 1018191617 188 WLKNEEPIDSEQDENIDTR-----ADHNLIIRQARLSDSGNYTCMAANIVAKRRSlSATVVV 244
Cdd:cd04970    38 WSFNGVPIDLEKIEGHYRRrygkdSNGDLEIVNAQLKHAGRYTCTAQTVVDSDSA-SATLVV 98

Immunoglobulin (Ig)-like domain of vascular endothelial growth factor receptor (VEGFR); member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain of vascular endothelial growth factor receptor (VEGFR). The VEGFRs have an extracellular component with seven Ig-like domains, a transmembrane segment, and an intracellular tyrosine kinase domain interrupted by a kinase-insert domain. The VEGFR family consists of three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). VEGFRs bind VEGFs with high affinity at the Ig-like domains. VEGF-A is important to the growth and maintenance of vascular endothelial cells and to the development of new blood- and lymphatic-vessels in physiological and pathological states. VEGFR-2 is a major mediator of the mitogenic, angiogenic, and microvascular permeability-enhancing effects of VEGF-A. VEGFR-1 may play an inhibitory part in these processes by binding VEGF and interfering with its interaction with VEGFR-2. VEGFR-1 has a signaling role in mediating monocyte chemotaxis. VEGFR-1 and VEGFR-2 may mediate a chemotactic and a survival signal in hematopoietic stem cells or leukemia cells. VEGFR-3 has been shown to be involved in tumor angiogenesis and growth. 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 1018191617 180 GVPAAEVEWLKNEEPIDseqdENIDTRADHNLIIRQARLSDSGNYTCMAANIVAK-RRSLSATVVV 244
Cdd:cd04976    29 AYPPPEVVWYKDGLPLT----EKARYLTRHSLIIKEVTEEDTGNYTILLSNKQSNvFKNLTATLVV 90

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

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gi 1018191617 171 IVLHCRPpEGVPAAEVEWLKNEEPIDSEQdENIdTRADHNLIIRQARLSDSGNYTCMAANIVAKRRSlSATVVV 244
Cdd:cd20978    19 VTLPCQV-TGVPQPKITWLHNGKPLQGPM-ERA-TVEDGTLTIINVQPEDTGYYGCVATNEIGDIYT-ETLLHV 88

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.

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gi 1018191617 167 IEG-MIVLHCRPpEGVPAAEVEWLKNEEPIDsEQDENIDTRAD-HNLIIRQARLSDSGNYTCMAANIVAKRRSLSATVVV 244
Cdd:cd20970    15 REGeNATFMCRA-EGSPEPEISWTRNGNLII-EFNTRYIVRENgTTLTIRNIRRSDMGIYLCIASNGVPGSVEKRITLQV 92

First immunoglobulin (Ig) domain of contactin-1; member of the I-set of Ig superfamily domains; The members here are composed of the first immunoglobulin (Ig) domain of the neural cell adhesion molecule contactin-1. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. 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.

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gi 1018191617 156 FEQDPQGREVP---IEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENidTRADHNLIIRQA-RLSDSGNYTCMAANI 231
Cdd:cd05849     4 FEEQPIDTIYPeesTEGKVSVNCRA-RANPFPIYKWRKNNLDIDLTNDRY--SMVGGNLVINNPdKYKDAGRYVCIVSNI 80

                          90
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gi 1018191617 232 VAKRRSLSATV 242
Cdd:cd05849    81 YGKVRSREATL 91

Death domain of Nuclear Factor-KappaB precursor proteins; Death Domain (DD) of Nuclear Factor-KappaB (NF-kB) precursor proteins. The NF-kB family of transcription factors play a central role in cardiovascular growth, stress response, and inflammation by controlling the expression of a network of different genes. There are five NF-kB proteins, all containing an N-terminal REL Homology Domain (RHD). Two of these, NF-kB1 and NF-kB2 are produced from the processing of the precursor proteins p105 and p100, respectively. In addition to RHD, p105 and p100 contain ANK repeats and a C-terminal DD. NF-kBs are regulated by the Inhibitor of NF-kB (IkB) Kinase (IKK) complex through classical and non-canonical pathways, which differ in the IKK subunits involved and downstream targets. IKKs facilitate the release of NF-kB dimers from an inactive state, allowing them to migrate to the nucleus where they regulate gene transcription. The precursor proteins p105 and p100 function as IkBs and as NF-kB proteins after being processed by the proteasome. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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gi 1018191617 852 IRQRICATFDtpnaKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEarhQHDGDLDSLACALEEIGRT 923
Cdd:cd08310     1 TRLRLCKLLD----VGKDWRELAELLGLGHLVESIEQSSSPTKLLLDYYE---AQGGTLEKLREALRALGET 65

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor, and similar domains; member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor. FGF receptors bind FGF signaling polypeptides. FGFs participate in multiple processes such as morphogenesis, development, and angiogenesis. FGFs bind to four FGF receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4). Receptor diversity is controlled by alternative splicing producing splice variants with different ligand binding characteristics and different expression patterns. FGFRs have an extracellular region comprised of three Ig-like domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding and specificity reside in the Ig-like domains 2 and 3, and the linker region that connects these two. FGFR activation and signaling depend on FGF-induced dimerization, a process involving cell surface heparin or heparin sulfate proteoglycans. This group also contains fibroblast growth factor (FGF) receptor like-1(FGFRL1). FGFRL1 does not have a protein tyrosine kinase domain at its C-terminus; neither does its cytoplasmic domain appear to interact with a signaling partner. It has been suggested that FGFRL1 may not have any direct signaling function, but instead acts as a decoy receptor trapping FGFs and preventing them from binding other receptors.

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gi 1018191617 165 VPIEGMIVLHCrPPEGVPAAEVEWLKNEEPIDSEQDENI-DTRADH-NLIIRQARLSDSGNYTCMAAN 230
Cdd:cd05729    16 LPAANKVRLEC-GAGGNPMPNITWLKDGKEFKKEHRIGGtKVEEKGwSLIIERAIPRDKGKYTCIVEN 82

immunoglobulin-like domain of telokin and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin (Ig) domain in telokin, the C-terminal domain of myosin light chain kinase which is identical to telokin, and similar proteins. 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 telokin Ig domain 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 1018191617 179 EGVPAAEVEWLKNEEPIDSEQDENIDTRADHN--LIIRQARLSDSGNYTCMAANiVAKRRSLSATVVV 244
Cdd:cd20973    22 EGYPDPEVKWMKDDNPIVESRRFQIDQDEDGLcsLIISDVCGDDSGKYTCKAVN-SLGEATCSAELTV 88