Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 424 PDEPFNLTMTNSTLNTISVAWE-PRFDGGSDQIFEVKYRRQNDDLIHLVNT---THTNLRLSGLATANTYFFQIRSINAR 499
Cdd:cd00063     1 PSPPTNLRVTDVTSTSVTLSWTpPEDDGGPITGYVVEYREKGSGDWKEVEVtpgSETSYTLTGLKPGTEYEFRVRAVNGG 80

                          90
                  ....*....|....
gi 1017483962 500 GFaSSWTSPVIFAT 513
Cdd:cd00063    81 GE-SPPSESVTVTT 93

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 1017483962 338 GGVAKARCKVYAVPTVEFVWEKDEQLIkKNSSKYsivntQIDYSTYESTLWIKNIVPDD---YTkkvkCIARNSFGTD 412
Cdd:pfam07679  15 GESARFTCTVTGTPDPEVSWFKDGQPL-RSSDRF-----KVTYEGGTYTLTISNVQPDDsgkYT----CVATNSAGEA 82

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 1017483962  30 PPRRVLIrpaDSGDQRLLVGKSARLVCGTLSSNPAAHISWqfsraTDDNKVHLGDVSLnETTRDNGFNVENVLSFTPTEE 109
Cdd:cd05883     3 PPRNLVI---DIQKDTAVEGEEIELNCTAMASKPAATIRW-----FKGNKELTGKSEV-EEWYSRMFTVTSQLMLKVTKE 73

                          90
                  ....*....|....*.
gi 1017483962 110 YDGTVVHCIANHPEWK 125
Cdd:cd05883    74 DDGVPVICLVDHPAVK 89

Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 424 PDEPFNLTMTNSTLNTISVAWE-PRFDGGSDQIFEVKYRRQNDDLIHLVNT---THTNLRLSGLATANTYFFQIRSINAR 499
Cdd:cd00063     1 PSPPTNLRVTDVTSTSVTLSWTpPEDDGGPITGYVVEYREKGSGDWKEVEVtpgSETSYTLTGLKPGTEYEFRVRAVNGG 80

                          90
                  ....*....|....
gi 1017483962 500 GFaSSWTSPVIFAT 513
Cdd:cd00063    81 GE-SPPSESVTVTT 93

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  238 STPVIAATGDTVLLECEADGEPSkaNMIHWYKNGEILAAQ------HRGHKKAILRL-NATEQQSGEYTCKADNGIGVpA 310
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPP--PEVTWYKQGGKLLAEsgrfsvSRSGSTSTLTIsNVTPEDSGTYTCAATNSSGS-A 77

                   ....*...
gi 1017483962  311 EGQTFLLV 318
Cdd:smart00410  78 SSGTTLTV 85

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM), and similar domains; The members here are composed of the third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM). L1 belongs to the L1 subfamily of cell adhesion molecules (CAMs) and is comprised of an extracellular region having six Ig-like domains and five fibronectin type III domains, a transmembrane region and an intracellular domain. L1 is primarily expressed in the nervous system and is involved in its development and function. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM and human neurofascin.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1017483962 238 STPVIAATGDTVLLECEADGEPSKAnmIHWYK-NGEILA--AQHRGHKKAILRLNATEQQSGEYTCKADNGIG 307
Cdd:cd05731     2 ESSTMVLRGGVLLLECIAEGLPTPD--IRWIKlGGELPKgrTKFENFNKTLKIENVSEADSGEYQCTASNTMG 72

Fifth immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3 (also known as Neph2). This protein has five Ig-like domains, one transmembrane domain, and a cytoplasmic tail. Included in this group is mammalian Kirrel (also known as Neph1), Kirrel2 (also known as Neph3), and Drosophila RST (also known as irregular chiasm C-roughest) protein. These proteins contain multiple Ig domains, have properties of cell adhesion molecules, and are important in organ development.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1017483962 336 ILGGVAKARCKVYAVPTVE-FVWEKDEQLIKKNSSKYSIVNTQIDYSTYESTLWIKNIVPDDYTKKVKCIARNSFGTD 412
Cdd:cd05758    14 ILGEKARLECLVFSSPPPDrIVWSWDEGFLESGSSGRFSVETFPTEPGVISVLHISGTQRSDFQTSFNCSAWNRFGEG 91

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 147 PVTVVMSEGDSFKENLTVRGNPAISLwQWRKNGVPF--DHTIgRVFARG--AVLSGKQLLSTDAGVYTLTATNSVGSTNI 222
Cdd:pfam07679   7 PKDVEVQEGESARFTCTVTGTPDPEV-SWFKDGQPLrsSDRF-KVTYEGgtYTLTISNVQPDDSGKYTCVATNSAGEAEA 84

                  ....*.
gi 1017483962 223 TIKLAV 228
Cdd:pfam07679  85 SAELTV 90

Second immunoglobulin (Ig)-like domain of nectin-like molecule 2 (Necl-2); member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of nectin-like molecule 2 (Necl-2; also known as cell adhesion molecule 1 (CADM1)). Nectin-like molecules (Necls) have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. Necl-2 has Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-1 is expressed in a wide variety of tissues and is a putative tumour suppressor gene which is downregulated in aggressive neuroblastoma. Ig domains are likely to participate in ligand binding and recognition.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  30 PPRRVLIrpaDSGDQRLLVGKSARLVCGTLSSNPAAHISWqfsraTDDNKVHLGDVSLnETTRDNGFNVENVLSFTPTEE 109
Cdd:cd05883     3 PPRNLVI---DIQKDTAVEGEEIELNCTAMASKPAATIRW-----FKGNKELTGKSEV-EEWYSRMFTVTSQLMLKVTKE 73

                          90
                  ....*....|....*.
gi 1017483962 110 YDGTVVHCIANHPEWK 125
Cdd:cd05883    74 DDGVPVICLVDHPAVK 89

Fourth Ig-like domain from smooth muscle myosin light chain kinase and similar domains ; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain from smooth muscle myosin light chain kinase (MYLK) and similar domains. 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 this group shows that the fourth Ig-like domain from myosin light chain kinase lacks this strand and thus 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1017483962 154 EGDSFKENLTVRGNPaISLWQWRKNGVPFDHTIGRVFARGAV--LSGKQLLSTDAGVYTLTATNSVGSTNITIKLAV 228
Cdd:cd20976    15 EGQDFVAQCSARGKP-VPRITWIRNAQPLQYAADRSTCEAGVgeLHIQDVLPEDHGTYTCLAKNAAGQVSCSAWVTV 90

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  337 LGGVAKARCKVYAVPTVEFVWEKDEQLIKKNSSKYSivntqIDYSTYESTLWIKNIVPDD---YTkkvkCIARNSFGTDH 413
Cdd:smart00410   8 EGESVTLSCEASGSPPPEVTWYKQGGKLLAESGRFS-----VSRSGSTSTLTISNVTPEDsgtYT----CAATNSSGSAS 78

Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 424 PDEPFNLTMTNSTLNTISVAWE-PRFDGGSDQIFEVKYRRQNDDLIHLVNT---THTNLRLSGLATANTYFFQIRSINAR 499
Cdd:cd00063     1 PSPPTNLRVTDVTSTSVTLSWTpPEDDGGPITGYVVEYREKGSGDWKEVEVtpgSETSYTLTGLKPGTEYEFRVRAVNGG 80

                          90
                  ....*....|....
gi 1017483962 500 GFaSSWTSPVIFAT 513
Cdd:cd00063    81 GE-SPPSESVTVTT 93

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 233 RITSISTPVIAATGDTVLLECEADGEPSKAnmIHWYKNGEILAAQHRGHKKAI-----LRL-NATEQQSGEYTCKADNGI 306
Cdd:pfam07679   2 KFTQKPKDVEVQEGESARFTCTVTGTPDPE--VSWFKDGQPLRSSDRFKVTYEggtytLTIsNVQPDDSGKYTCVATNSA 79

                  .
gi 1017483962 307 G 307
Cdd:pfam07679  80 G 80

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1017483962 338 GGVAKARCKVYAVPTVEFVWEKDEQLIkKNSSKYsivntQIDYSTYESTLWIKNIVPDD---YTkkvkCIARNSFGTD 412
Cdd:pfam07679  15 GESARFTCTVTGTPDPEVSWFKDGQPL-RSSDRF-----KVTYEGGTYTLTISNVQPDDsgkYT----CVATNSAGEA 82

Fibronectin type 3 domain; One of three types of internal repeat within the plasma protein, fibronectin. The tenth fibronectin type III repeat contains a RGD cell recognition sequence in a flexible loop between 2 strands. Type III modules are present in both extracellular and intracellular proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  424 PDEPFNLTMTNSTLNTISVAWE-PRFDGGSDQI--FEVKYRRQNDDLIHL-VNTTHTNLRLSGLATANTYFFQIRSINAR 499
Cdd:smart00060   1 PSPPSNLRVTDVTSTSVTLSWEpPPDDGITGYIvgYRVEYREEGSEWKEVnVTPSSTSYTLTGLKPGTEYEFRVRAVNGA 80

                   .
gi 1017483962  500 G 500
Cdd:smart00060  81 G 81

Fibronectin type III domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 425 DEPFNLTMTNSTLNTISVAWEPRFDGGSD-QIFEVKYRRQNDDL----IHLVNTTHTnLRLSGLATANTYFFQIRSINAR 499
Cdd:pfam00041   1 SAPSNLTVTDVTSTSLTVSWTPPPDGNGPiTGYEVEYRPKNSGEpwneITVPGTTTS-VTLTGLKPGTEYEVRVQAVNGG 79

                  ..
gi 1017483962 500 GF 501
Cdd:pfam00041  80 GE 81

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM); The members here are composed of the third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM). L1 belongs to the L1 subfamily of cell adhesion molecules (CAMs) and is comprised of an extracellular region having six Ig-like domains, five fibronectin type III domains, a transmembrane region and an intracellular domain. L1 is primarily expressed in the nervous system and is involved in its development and function. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, or spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1017483962 238 STPVIAATGDTVLLECEADGEPSKAnmIHWYK-NGEILAAQ--HRGHKKAILRLNATEQQSGEYTCKADNGIG 307
Cdd:cd05876     2 SSSLVALRGQSLVLECIAEGLPTPT--VKWLRpSGPLPPDRvkYQNHNKTLQLLNVGESDDGEYVCLAENSLG 72

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 147 PVTVVMSEGDSFKENLTVRGNPAISLwQWRKNGVPF--DHTIgRVFARG--AVLSGKQLLSTDAGVYTLTATNSVGSTNI 222
Cdd:pfam07679   7 PKDVEVQEGESARFTCTVTGTPDPEV-SWFKDGQPLrsSDRF-KVTYEGgtYTLTISNVQPDDSGKYTCVATNSAGEAEA 84

                  ....*.
gi 1017483962 223 TIKLAV 228
Cdd:pfam07679  85 SAELTV 90

First immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs), and similar domains; The members here are composed of the first immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs). Interactions between IgG and FcgammaR are important to the initiation of cellular and humoral response. IgG binding to FcgammaR leads to a cascade of signals and ultimately to functions such as antibody-dependent-cellular-cytotoxicity (ADCC), endocytosis, phagocytosis, release of inflammatory mediators, etc. FcgammaR has two Ig-like domains. This group also contains FcepsilonRI which binds IgE with high affinity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1017483962 245 TGDTVLLECEADGePSKANMIHWYKNGEILAAQHrghkKAILRLNATEQQSGEYTCKADNG 305
Cdd:cd05752    14 QGEKVTLTCQGFY-SPEQNSTQWYHNGTLISSTS----SSYRIVAATVNDSGEYRCQTQGS 69

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1017483962 246 GDTVLLECEADgEPSKANMIHWYKNGEILAAQHRGHKKA-------ILRLNATEQQSGEYTCKADNGIGVP 309
Cdd:pfam00047  11 GDSATLTCSAS-TGSPGPDVTWSKEGGTLIESLKVKHDNgrttqssLLISNVTKEDAGTYTCVVNNPGGSA 80

Fourth Ig domain of the neural cell adhesion molecule contactin-2, and similar domains; The members here are composed of the fourth Ig domain of the neural cell adhesion molecule contactin-2. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. Contactin-2 (also called TAG-1, axonin-1) facilitates cell adhesion by homophilic binding between molecules in apposed membranes. The first four Ig domains form the intermolecular binding fragment which arranges as a compact U-shaped module by contacts between Ig domains 1 and 4, and domains 2 and 3. It has been proposed that a linear zipper-like array forms, from contactin-2 molecules alternatively provided by the two apposed membranes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1017483962 243 AATGDTVLLECEADGEPSKAnmIHWYKNGEILAAQHR----GHKKAILRLNATEqqSGEYTCKADN 304
Cdd:cd05728    11 ADIGSSLRWECKASGNPRPA--YRWLKNGQPLASENRieveAGDLRITKLSLSD--SGMYQCVAEN 72

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 231 SARITSISTPVIAATGDTVLLECEADGEPSKanMIHWYKNGEILAAQHRGH-----KKAILRLNATEQQSGEYTCKADNG 305
Cdd:cd05730     3 TIRARQSEVNATANLGQSVTLACDADGFPEP--TMTWTKDGEPIESGEEKYsfnedGSEMTILDVDKLDEAEYTCIAENK 80

                  ..
gi 1017483962 306 IG 307
Cdd:cd05730    81 AG 82

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 233 RITSISTPVIAAtGDTVLLECEADGEpSKANMIHWYKNGEILAAQH-------RGHKKAILRLN-ATEQQSGEYTCKADN 304
Cdd:cd05750     2 KLKEMKSQTVQE-GSKLVLKCEATSE-NPSPRYRWFKDGKELNRKRpknikirNKKKNSELQINkAKLEDSGEYTCVVEN 79

                  ...
gi 1017483962 305 GIG 307
Cdd:cd05750    80 ILG 82

Immunoglobulin-like domain of human nephrin and similar proteins; member of the C1-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin-like domain in human nephrin and similar proteins. Nephrin is an integral component of the slit diaphragm and is a central component of the glomerular ultrafilter. Nephrin plays a structural role and has a role in signaling. Nephrin is a transmembrane protein having a short intracellular portion, an extracellular portion comprised of eight Ig-like domains, and one fibronectin type III-like domain. The extracellular portions of nephrin from neighboring foot processes of separate podocyte cells may interact with each other, and in association with other components of the slit diaphragm form a porous molecular sieve within the slit pore. The intracellular portion of nephrin is associated with linker proteins, which connect nephrin to the actin cytoskeleton. The intracellular portion is tyrosine phosphorylated, and mediates signaling from the slit diaphragm into the podocytes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 340 VAKARCKVYAVPTVEFVWEKDEQLIKKNSSKYSiVNTQIDYSTYESTLWIKNI-VPDDYTKkVKCIARNSFGTDHLSIPI 418
Cdd:cd05773    25 DANLVCQAQGVPRVQFRWAKNGVPLDLGNPRYE-ETTEHTGTVHTSILTIINVsAALDYAL-FTCTAHNSLGEDSLDIQL 102

                  ....*..
gi 1017483962 419 IPPTHPD 425
Cdd:cd05773   103 VSTSRPD 109

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 1017483962 344 RCKVYAVPTVEFVWEKDEQLIKKNSskysivNTQIDYSTYESTLWIKNIVPDDyTKKVKCIARNSFGT 411
Cdd:cd00096     4 TCSASGNPPPTITWYKNGKPLPPSS------RDSRRSELGNGTLTISNVTLED-SGTYTCVASNSAGG 64

Second immunoglobulin (Ig)-like domain of nectin-like molcule-1 (Necl-1); member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of nectin-like molcule-1 (Necl-1; also known as cell adhesion molecule3 (CADM3)). These nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. The N-terminal Ig-like domain of the extracellular region belongs to the V-type subfamily of Ig domains is essential to cell-cell adhesion and plays a part in the interaction with the envelope glycoprotein D of various viruses. Necl-1 and Necl-2 have Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-1 is specifically expressed in neural tissue and is important to the formation of synapses, axon bundles, and myelinated axons. Necl-2 is expressed in a wide variety of tissues and is a putative tumour suppressor gene which is downregulated in aggressive neuroblastoma. Ig domains are likely to participate in ligand binding and recognition.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  51 SARLVCGTLSSNPAAHISWQfsraTDDNKVHLGDVSLNETTRDNGFNVENVLSFTPTEEYDGTVVHCIANHPEWKHSVNT 130
Cdd:cd07705    21 KAKLRCTSSGSKPAANIKWR----KGDQELEGAPTSVQEDGNGKTFTVSSSVEFQVTREDDGAEITCSVGHESLHDSDRS 96

                  .
gi 1017483962 131 S 131
Cdd:cd07705    97 T 97

Second immunoglobulin (Ig)-like domain of the nectin-like molecules Necl-1 - Necl-4; member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of the nectin-like molecules Necl-1 (also known as cell adhesion molecule 3 or CADM3), Necl-2 (also known as CADM1), Necl-3 (also known as CADM2) and Necl-4 (also known as CADM4). These nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. The N-terminal Ig-like domain of the extracellular region belongs to the V-type subfamily of Ig domains, is essential to cell-cell adhesion, and plays a part in the interaction with the envelope glycoprotein D of various viruses. Necl-1 and Necl-2 have Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-1 is specifically expressed in neural tissue and is important to the formation of synapses, axon bundles, and myelinated axons. Necl-2 is expressed in a wide variety of tissues, and is a putative tumour suppressor gene, which is downregulated in aggressive neuroblastoma. Necl-3 has been shown to accumulate in tissues of the central and peripheral nervous system, where it is expressed in ependymal cells and myelinated axons. It is observed at the interface between the axon shaft and the myelin sheath. Necl-4 is expressed on Schwann cells, and plays a key part in initiating peripheral nervous system (PNS) myelination. Necl-4 participates in cell-cell adhesion and is proposed to play a role in tumor suppression.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  49 GKSARLVCGTLSSNPAAHISWQfsraTDDNKVHlGDVSLNETTRDNGFNVENVLSFTPTEEYDGTVVHCIANHPEWK-HS 127
Cdd:cd05761    19 GDEITLTCTTSGSKPAADIRWF----KNDKELK-GVKEVQESGAGKTFTVTSTLRFRVDRDDDGVAVICRVDHESLTsTP 93

                  ....*....
gi 1017483962 128 VNTSFPLNV 136
Cdd:cd05761    94 KQTQQVLEV 102

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 149 TVVMSEGDSFKENLTVRGNPA--ISlwqWRKNGVPFDHTiGRVF----ARGAVLSGKQLLSTDAGVYTLTATNSVGSTNI 222
Cdd:cd05748     1 TIVVRAGESLRLDIPIKGRPTptVT---WSKDGQPLKET-GRVQiettASSTSLVIKNAKRSDSGKYTLTLKNSAGEKSA 76

                  ....*.
gi 1017483962 223 TIKLAV 228
Cdd:cd05748    77 TINVKV 82

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962 139 PPKmLVNDPVTVVMSEGDSFKENLTVRGNPAISLWqWRKNGVPFDHTIGRVFAR---GAVLSGKQLLSTDAGVYTLTATN 215
Cdd:pfam13927   1 KPV-ITVSPSSVTVREGETVTLTCEATGSPPPTIT-WYKNGEPISSGSTRSRSLsgsNSTLTISNVTRSDAGTYTCVASN 78

Sixth 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 sixth 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1017483962 165 RGNPAISLwQWRKNGVPF--DH--TIGRVFARGAVLSGKQLLSTDAGVYTLTATNSVGSTNITIKLAV 228
Cdd:cd20959    28 GGDLPLNI-RWTLDGQPIsdDLgiTVSRLGRRSSILSIDSLEASHAGNYTCHARNSAGSASYTAPLTV 94

Third immunoglobulin (Ig)-like domain of fibroblast growth factor receptor (FGFR); member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig)-like domain of fibroblast growth factor receptor (FGFR). Fibroblast growth factors (FGFs) participate in morphogenesis, development, angiogenesis, and wound healing. These FGF-stimulated processes are mediated by four FGFR tyrosine kinases (FGRF1-4). FGFRs are comprised of an extracellular portion consisting of three Ig-like domains, a transmembrane helix, and a cytoplasmic portion having protein tyrosine kinase activity. The highly conserved Ig-like domains 2 and 3, and the linker region between D2 and D3 define a general binding site for FGFs. 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 1017483962 331 AKTAGILGGVAKARCKVYAVPTVEFVWEKdeqLIKKNSSKYSIVNT---------QIDYSTYESTLWIKNIVPDD---YT 398
Cdd:cd04974     9 ANQTVVLGSDVEFHCKVYSDAQPHIQWLK---HVEVNGSKYGPDGLpyvtvlkvaGVNTTGEENTLTISNVTFDDageYI 85

                          90
                  ....*....|....*..
gi 1017483962 399 kkvkCIARNSFGTDHLS 415
Cdd:cd04974    86 ----CLAGNSIGLSFHS 98

Second immunoglobulin (Ig)-like domain of a Follistatin-related protein 5, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain found in human Follistatin-related protein 5 (FSTL5) and a follistatin-like molecule encoded by the CNS-related Mahya gene. Mahya genes have been retained in certain Bilaterian branches during evolution. They are conserved in Hymenoptera and Deuterostomes, but are absent from other metazoan species such as fruit fly and nematode. Mahya proteins are secretory, with a follistatin-like domain (Kazal-type serine/threonine protease inhibitor domain and EF-hand calcium-binding domain), two Ig-like domains, and a novel C-terminal domain. Mahya may be involved in learning and memory and in processing of sensory information in Hymenoptera and vertebrates. Follistatin is a secreted, multidomain protein that binds activins with high affinity and antagonizes their signaling.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1017483962 246 GDTVLLECEADGEPSKanMIHWYKNGEilAAQHRGHKKAILRLNATE--------QQSGEYTCKADNGIGV 308
Cdd:cd05736    15 GVEASLRCHAEGIPLP--RVQWLKNGM--DINPKLSKQLTLIANGSElhisnvryEDTGAYTCIAKNEGGV 81

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1017483962  147 PVTVVMSEGDSFkeNLT--VRGNPAISLWqWRKNGVPFDHTIGRVFARGAVLSG----KQLLSTDAGVYTLTATNSVGST 220
Cdd:smart00410   1 PPSVTVKEGESV--TLSceASGSPPPEVT-WYKQGGKLLAESGRFSVSRSGSTStltiSNVTPEDSGTYTCAATNSSGSA 77

                   ....*...
gi 1017483962  221 NITIKLAV 228
Cdd:smart00410  78 SSGTTLTV 85