Fifth domain (immunoglobulin-like) of Trk receptors TrkA, TrkB, and TrkC; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth domain of Trk receptors TrkA, TrkB, and TrkC, an immunoglobulin (Ig)-like domain which binds to neurotrophin. The Trk family of receptors are tyrosine kinase receptors. They are activated by dimerization, leading to autophosphorylation of intracellular tyrosine residues, and triggering the signal transduction pathway. TrkA, TrkB, and TrkC share significant sequence homology and domain organization. The first three domains are leucine-rich domains while the fourth and fifth domains are Ig-like domains playing a part in ligand binding. TrkA, TrkB, and TrkC mediate the trophic effects of the neurotrophin Nerve Growth Factor (NGF) family. TrkA is recognized by NGF. TrkB is recognized by brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-4. TrkC is recognized by NT-3. NT-3 is promiscuous as in some cell systems it activates TrkA and TrkB receptors. TrkA is a receptor found in all major NGF targets, including the sympathetic, trigeminal, and dorsal root ganglia, cholinergic neurons of the basal forebrain, and the striatum. TrKB transcripts are found throughout multiple structures of the central and peripheral nervous systems. The TrkC gene is expressed throughout the mammalian nervous system. This group belongs to the I-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 304 PPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEG---EISEGCLLFNKPTHYNNGNYTLIA 380
Cdd:cd04971    1 APVIVRLEEPELRHHWCIPFTVRGNPKPTLTWYHNGAVLNESDYIRTEIHYEAatpTEYHGCLKFDNPTHVNNGNYTLVA 80

                         90
                 ....*....|....*.
gi 992319530 381 KNPLGTANQTINGHFL 396
Cdd:cd04971   81 SNEYGQDSKSISAHFM 96

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530  214 VSHVNLTVREGDNAVITCNGS-GSPLPDVDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGfTLTCIAENVVGM 292
Cdd:pfam00047   1 SAPPTVTVLEGDSATLTCSAStGSPGPDVTWSKEGGTLIESLKVKHDNGRTTQSSLLISNVTKEDAG-TYTCVVNNPGGS 79

                  ....*..
gi 992319530  293 SNASVAL 299
Cdd:pfam00047  80 ATLSTSL 86

Leucine rich repeat N-terminal domain; Leucine Rich Repeats pfam00560 are short sequence motifs present in a number of proteins with diverse functions and cellular locations. Leucine Rich Repeats are often flanked by cysteine rich domains. This domain is often found at the N-terminus of tandem leucine rich repeats.

                          10        20
                  ....*....|....*....|.
gi 992319530   31 ACPANCVCSKTEINCRRPDDG 51
Cdd:pfam01462   1 ACPVPCHCSATVVNCSDRGLT 21

Fifth domain (immunoglobulin-like) of Trk receptors TrkA, TrkB, and TrkC; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth domain of Trk receptors TrkA, TrkB, and TrkC, an immunoglobulin (Ig)-like domain which binds to neurotrophin. The Trk family of receptors are tyrosine kinase receptors. They are activated by dimerization, leading to autophosphorylation of intracellular tyrosine residues, and triggering the signal transduction pathway. TrkA, TrkB, and TrkC share significant sequence homology and domain organization. The first three domains are leucine-rich domains while the fourth and fifth domains are Ig-like domains playing a part in ligand binding. TrkA, TrkB, and TrkC mediate the trophic effects of the neurotrophin Nerve Growth Factor (NGF) family. TrkA is recognized by NGF. TrkB is recognized by brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-4. TrkC is recognized by NT-3. NT-3 is promiscuous as in some cell systems it activates TrkA and TrkB receptors. TrkA is a receptor found in all major NGF targets, including the sympathetic, trigeminal, and dorsal root ganglia, cholinergic neurons of the basal forebrain, and the striatum. TrKB transcripts are found throughout multiple structures of the central and peripheral nervous systems. The TrkC gene is expressed throughout the mammalian nervous system. This group belongs to the I-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 304 PPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEG---EISEGCLLFNKPTHYNNGNYTLIA 380
Cdd:cd04971    1 APVIVRLEEPELRHHWCIPFTVRGNPKPTLTWYHNGAVLNESDYIRTEIHYEAatpTEYHGCLKFDNPTHVNNGNYTLVA 80

                         90
                 ....*....|....*.
gi 992319530 381 KNPLGTANQTINGHFL 396
Cdd:cd04971   81 SNEYGQDSKSISAHFM 96

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530  214 VSHVNLTVREGDNAVITCNGS-GSPLPDVDWIVTGLQSINTHQTNLNWTNVHAINLTLVNVTSEDNGfTLTCIAENVVGM 292
Cdd:pfam00047   1 SAPPTVTVLEGDSATLTCSAStGSPGPDVTWSKEGGTLIESLKVKHDNGRTTQSSLLISNVTKEDAG-TYTCVVNNPGGS 79

                  ....*..
gi 992319530  293 SNASVAL 299
Cdd:pfam00047  80 ATLSTSL 86

Leucine rich repeat;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 992319530  103 TGLQKLTIKNSGLRSIQPRAFAKNPHLRYINLSSNRLTTLSWQLFQTL-SLRELQLEQN 160
Cdd:pfam13855   1 PNLRSLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLpSLRYLDLSGN 59

Leucine rich repeat C-terminal domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 992319530   160 NFFNCSCDIRWMQLWQEQGEAKLNSQNLYCINADGSQLPLFRMNIS 205
Cdd:smart00082   1 NPFICDCELRWLLRWLQANEHLQDPVDLRCASPSSLRGPLLELLHS 46

Leucine-rich repeat (LRR) protein [Transcription];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530  75 DISRN-ITSI--HIENWRSLHTLNAVDMEL---------YTGLQKLTIKNSGLRSIqPRAFAKNPHLRYINLSSNRLTTL 142
Cdd:COG4886  119 DLSGNqLTDLpeELANLTNLKELDLSNNQLtdlpeplgnLTNLKSLDLSNNQLTDL-PEELGNLTNLKELDLSNNQITDL 197

                         90
                 ....*....|....*...
gi 992319530 143 SWQLFQTLSLRELQLEQN 160
Cdd:COG4886  198 PEPLGNLTNLEELDLSGN 215

Leucine rich repeat N-terminal domain; Leucine Rich Repeats pfam00560 are short sequence motifs present in a number of proteins with diverse functions and cellular locations. Leucine Rich Repeats are often flanked by cysteine rich domains. This domain is often found at the N-terminus of tandem leucine rich repeats.

                          10        20
                  ....*....|....*....|.
gi 992319530   31 ACPANCVCSKTEINCRRPDDG 51
Cdd:pfam01462   1 ACPVPCHCSATVVNCSDRGLT 21

Fifth domain (immunoglobulin-like) of Trk receptors TrkA, TrkB, and TrkC; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth domain of Trk receptors TrkA, TrkB, and TrkC, an immunoglobulin (Ig)-like domain which binds to neurotrophin. The Trk family of receptors are tyrosine kinase receptors. They are activated by dimerization, leading to autophosphorylation of intracellular tyrosine residues, and triggering the signal transduction pathway. TrkA, TrkB, and TrkC share significant sequence homology and domain organization. The first three domains are leucine-rich domains while the fourth and fifth domains are Ig-like domains playing a part in ligand binding. TrkA, TrkB, and TrkC mediate the trophic effects of the neurotrophin Nerve Growth Factor (NGF) family. TrkA is recognized by NGF. TrkB is recognized by brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-4. TrkC is recognized by NT-3. NT-3 is promiscuous as in some cell systems it activates TrkA and TrkB receptors. TrkA is a receptor found in all major NGF targets, including the sympathetic, trigeminal, and dorsal root ganglia, cholinergic neurons of the basal forebrain, and the striatum. TrKB transcripts are found throughout multiple structures of the central and peripheral nervous systems. The TrkC gene is expressed throughout the mammalian nervous system. This group belongs to the I-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 304 PPRVVSLEEPELRLEHCIEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEG---EISEGCLLFNKPTHYNNGNYTLIA 380
Cdd:cd04971    1 APVIVRLEEPELRHHWCIPFTVRGNPKPTLTWYHNGAVLNESDYIRTEIHYEAatpTEYHGCLKFDNPTHVNNGNYTLVA 80

                         90
                 ....*....|....*.
gi 992319530 381 KNPLGTANQTINGHFL 396
Cdd:cd04971   81 SNEYGQDSKSISAHFM 96

Leucine rich repeat C-terminal motif; This entry represents the Leucine Rich Repeat C-terminal (LRRCT) capping motif from TRK receptors.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 992319530  163 NCSCDIRWMQLWQEQGEAKLNSQNLYCINaDGSQLPLFRMNISQCD 208
Cdd:pfam16920   1 RCSCDIRWLQLWQEEGLAGLGTQQLYCLN-DGSKIPLQSMNIPNCG 45

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530   218 NLTVREGDNAVITCNGSGSPLPDVDWIVTGLQSInTHQTNLNWTNVHAI-NLTLVNVTSEDNGfTLTCIAENVVGMSNAS 296
Cdd:smart00410   3 SVTVKEGESVTLSCEASGSPPPEVTWYKQGGKLL-AESGRFSVSRSGSTsTLTISNVTPEDSG-TYTCAATNSSGSASSG 80

                   ....*
gi 992319530   297 VALTV 301
Cdd:smart00410  81 TTLTV 85

Leucine rich repeat;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 992319530  103 TGLQKLTIKNSGLRSIQPRAFAKNPHLRYINLSSNRLTTLSWQLFQTL-SLRELQLEQN 160
Cdd:pfam13855   1 PNLRSLDLSNNRLTSLDDGAFKGLSNLKVLDLSNNLLTTLSPGAFSGLpSLRYLDLSGN 59

Leucine rich repeat C-terminal domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 992319530   160 NFFNCSCDIRWMQLWQEQGEAKLNSQNLYCINADGSQLPLFRMNIS 205
Cdd:smart00082   1 NPFICDCELRWLLRWLQANEHLQDPVDLRCASPSSLRGPLLELLHS 46

Fourth domain (immunoglobulin-like) of Trk receptors TrkA, TrkB, and TrkC; The members here are composed of the fourth domain of Trk receptors TrkA, TrkB, and TrkC, an immunoglobulin (Ig)-like domain which binds to neurotrophin. The Trk family of receptors are tyrosine kinase receptors. They are activated by dimerization, leading to autophosphorylation of intracellular tyrosine residues, and triggering the signal transduction pathway. TrkA, TrkB, and TrkC share significant sequence homology and domain organization. The first three domains are leucine-rich domains while the fourth and fifth domains are Ig-like domains playing a part in ligand binding. TrkA, TrkB, and TrkC mediate the trophic effects of the neurotrophin Nerve Growth Factor (NGF) family. TrkA is recognized by NGF. TrKB is recognized by brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-4. TrkC is recognized by NT-3. NT-3 is promiscuous as in some cell systems it activates TrkA and TrkB receptors. TrkA is a receptor found in all major NGF targets, including the sympathetic, trigeminal, and dorsal root ganglia, cholinergic neurons of the basal forebrain, and the striatum. TrKB transcripts are found throughout multiple structures of the central and peripheral nervous systems. The TrkC gene is expressed throughout the mammalian nervous system.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 211 EISVSHVNLTVREGDNAVITCNGSGSPLPDVDWIVTGLQSintHQTNLNWTNVHAINLTLVNVTSEDNGFTLTCIAENVV 290
Cdd:cd04972    1 TLKIQMPNASVDVGDDVLLQCQVEGQGLEQAGWILTELEQ---SATVMKSGSLPSLGLTLANVTSDLNRKNVTCWAENDV 77

                         90
                 ....*....|.
gi 992319530 291 GMSNASVALTV 301
Cdd:cd04972   78 GRAEVSVQVNV 88

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 217 VNLTVREGDNAVITCNGSGSPLPDVDWIVTG--LQSINTHQTNLNwtnvhaiNLTLVNVTSEDNGfTLTCIAENVVGMSN 294
Cdd:cd05725    5 QNQVVLVDDSAEFQCEVGGDPVPTVRWRKEDgeLPKGRYEILDDH-------SLKIRKVTAGDMG-SYTCVAENMVGKIE 76

                 ....*..
gi 992319530 295 ASVALTV 301
Cdd:cd05725   77 ASATLTV 83

Immunoglobulin I-set domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 992319530  325 VRGNPPPTLHWLHNGQPLRESKIIHVEYyqEGEISEgcLLFNKPTHYNNGNYTLIAKNPLGTA 387
Cdd:pfam07679  24 VTGTPDPEVSWFKDGQPLRSSDRFKVTY--EGGTYT--LTISNVQPDDSGKYTCVATNSAGEA 82

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 992319530 325 VRGNPPPTLHWLHNGQPL-RESKIIHVEyyqegeisEGCLLFNKPTHYNNGNYTLIAKNPLGT 386
Cdd:cd20978   25 VTGVPQPKITWLHNGKPLqGPMERATVE--------DGTLTIINVQPEDTGYYGCVATNEIGD 79

Second C-terminal immunoglobulin (Ig)-like domain of palladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the C-terminal immunoglobulin (Ig)-like domain of palladin. Palladin belongs to the palladin-myotilin-myopalladin family. Proteins belonging to this family contain multiple Ig-like domains and function as scaffolds, modulating actin cytoskeleton. Palladin binds to alpha-actinin ezrin, vasodilator-stimulated phosphoprotein VASP, SPIN90 (also known as DIP or mDia interacting protein), and Src. Palladin also binds F-actin directly, via its Ig3 domain. Palladin is expressed as several alternatively spliced isoforms, having various combinations of Ig-like domains, in a cell-type-specific manner. It has been suggested that palladin's different Ig-like domains may be specialized for distinct functions. 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 992319530 218 NLTVREGDNAVITCNGSGSPLPDVDWIVTG--LQSINTHQTNLNWTNVHAinLTLVNVTSEDNGFtLTCIAENVVGMSNA 295
Cdd:cd20990    9 DLTVQEGKLCRMDCKVSGLPTPDLSWQLDGkpIRPDSAHKMLVRENGVHS--LIIEPVTSRDAGI-YTCIATNRAGQNSF 85

                 ....*.
gi 992319530 296 SVALTV 301
Cdd:cd20990   86 NLELVV 91

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 992319530 212 ISVSHVNLTVREGDNAVITCNGSGSPLPDVDWIVTGLQ--SINTHQTNLNWTnvhaiNLTLVNVTSEDNGfTLTCIAENV 289
Cdd:cd20952    2 ILQGPQNQTVAVGGTVVLNCQATGEPVPTISWLKDGVPllGKDERITTLENG-----SLQIKGAEKSDTG-EYTCVALNL 75

                         90
                 ....*....|..
gi 992319530 290 VGMSNASVALTV 301
Cdd:cd20952   76 SGEATWSAVLDV 87

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 992319530 324 VVRGNPPPTLHWLHNGQPLRESKIIHVEYYQegeiSEGCLLFNKPTHYNNGNYTLIAKNPLGTANQTI 391
Cdd:cd00096    6 SASGNPPPTITWYKNGKPLPPSSRDSRRSEL----GNGTLTISNVTLEDSGTYTCVASNSAGGSASAS 69

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 992319530 327 GNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISEgcLLFNKPTHYNNGNYTLIAKNPLGTANQTINGH 394
Cdd:cd05750   26 ENPSPRYRWFKDGKELNRKRPKNIKIRNKKKNSE--LQINKAKLEDSGEYTCVVENILGKDTVTGNVT 91

C-terminal immunoglobulin-like domain of the myosin-associated giant protein kinase Twitchin, and similar domains; member of the I-set IgSF domains; The members here are composed of the C-terminal immunoglobulin-like domain of the myosin-associated giant protein kinase Twitchin and similar proteins, including Caenorhabditis elegans and Aplysia californica Twitchin, Drosophila melanogaster Projectin, and similar proteins. These are very large muscle proteins containing multiple immunoglobulin (Ig)-like and fibronectin type III (FN3) domains and a single kinase domain near the C-terminus. In humans these proteins are called Titin. 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. The Ig-like domain of the Twitchin is a member of the I-set 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. 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 992319530 325 VRGNPPPTLHWLHNGQPLRESkiihVEYYQEGEISEGCLLFNKPTHYNNGNYTLIAKNPLGTANQ 389
Cdd:cd20949   23 VKGEPQPNVTWHFNGQPISAS----VADMSKYRILADGLLINKVTQDDTGEYTCRAYQVNSIASD 83

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 218 NLTVREGDNAVITCNGSGSPLPDVDWIVTGlQSINTHQTNLNWTNVHAINLTLVNVTSEDNGfTLTCIAENVVGMSNASV 297
Cdd:cd05747   12 SLTVSEGESARFSCDVDGEPAPTVTWMREG-QIIVSSQRHQITSTEYKSTFEISKVQMSDEG-NYTVVVENSEGKQEAQF 89

                 ...
gi 992319530 298 ALT 300
Cdd:cd05747   90 TLT 92

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530  304 PPRVVSLEEPELRLE------HCIefvVRGNPPPTLHWLHNGQPLRESKIihveYYQEGEISEGCLLFNKPTHYNNGNYT 377
Cdd:pfam13927   1 KPVITVSPSSVTVREgetvtlTCE---ATGSPPPTITWYKNGEPISSGST----RSRSLSGSNSTLTISNVTRSDAGTYT 73

                  ....*
gi 992319530  378 LIAKN 382
Cdd:pfam13927  74 CVASN 78

Fourth 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 fourth 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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 217 VNLTVREGDNAVITCNGSGSPLPDVDWIVTGLQSINTHQTNLnwtnVHAINLTLVNVTSEDNGFtLTCIAENVVGMSNAS 296
Cdd:cd05723    5 SNIYAHESMDIVFECEVTGKPTPTVKWVKNGDVVIPSDYFKI----VKEHNLQVLGLVKSDEGF-YQCIAENDVGNAQAS 79

                 ....*
gi 992319530 297 VALTV 301
Cdd:cd05723   80 AQLII 84

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 321 IEFVVRGNPPPTLHWLHNGQPLRESKIIHVeyYQEGEISEgcLLFNKPTHYNNGNYTLIAKNPLGTANQT 390
Cdd:cd20972   21 LECRVTGNPTPVVRWFCEGKELQNSPDIQI--HQEGDLHS--LIIAEAFEEDTGRYSCLATNSVGSDTTS 86

Leucine-rich repeat (LRR) protein [Transcription];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530  75 DISRN-ITSI--HIENWRSLHTLN-------AVDMELY--TGLQKLTIKNSGLRSIqPRAFAKNPHLRYINLSSNRLTTL 142
Cdd:COG4886  165 DLSNNqLTDLpeELGNLTNLKELDlsnnqitDLPEPLGnlTNLEELDLSGNQLTDL-PEPLANLTNLETLDLSNNQLTDL 243

                         90
                 ....*....|....*...
gi 992319530 143 SWqLFQTLSLRELQLEQN 160
Cdd:COG4886  244 PE-LGNLTNLEELDLSNN 260

Fourth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 210 PEISVSHVNLTVREGDNAVITCNGSGSPLPDVDWIVTGLQSINTHQTNLN-WTNVHAINLTLVNVTS---EDNGFtLTCI 285
Cdd:cd20956    2 PVLLETFSEQTLQPGPSVSLKCVASGNPLPQITWTLDGFPIPESPRFRVGdYVTSDGDVVSYVNISSvrvEDGGE-YTCT 80

                 ....*.
gi 992319530 286 AENVVG 291
Cdd:cd20956   81 ATNDVG 86

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 992319530 326 RGNPPPTLHWLHNGQPLRESKiIHVEyyqegEISEGCLLFNKPTHYNNGNYTLIAKNPLGT 386
Cdd:cd05724   23 RGHPEPTVSWRKDGQPLNLDN-ERVR-----IVDDGNLLIAEARKSDEGTYKCVATNMVGE 77

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 218 NLTVREGDNAVITCNGSGSPLPDVDWI-VTG-LQSINTHQTNLNWTnvhainLTLVNVTSEDNGfTLTCIAENVVGMSNA 295
Cdd:cd05731    4 STMVLRGGVLLLECIAEGLPTPDIRWIkLGGeLPKGRTKFENFNKT------LKIENVSEADSG-EYQCTASNTMGSARH 76

                 ....*.
gi 992319530 296 SVALTV 301
Cdd:cd05731   77 TISVTV 82

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 296 SVALTVYYPPRVVSLEEPELRLEHCIefvVRGNPPPTLHWLHNGQPLRESK---IIHVEYYQEGEIsegcllfNKPTHYN 372
Cdd:cd05747    1 TLPATILTKPRSLTVSEGESARFSCD---VDGEPAPTVTWMREGQIIVSSQrhqITSTEYKSTFEI-------SKVQMSD 70

                         90
                 ....*....|...
gi 992319530 373 NGNYTLIAKNPLG 385
Cdd:cd05747   71 EGNYTVVVENSEG 83

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530  210 PEISVShvNLTVREGDNAVITCNGSGSPLPDVDWiVTGLQSINTHQtnlnwtnvhaiNLTLVNVTSEDNGfTLTCIAEN- 288
Cdd:pfam13895   2 PVLTPS--PTVVTEGEPVTLTCSAPGNPPPSYTW-YKDGSAISSSP-----------NFFTLSVSAEDSG-TYTCVARNg 66

                          90
                  ....*....|...
gi 992319530  289 VVGMSNASVALTV 301
Cdd:pfam13895  67 RGGKVSNPVELTV 79

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 321 IEFVVRGNPPPTLHWLHNGQPLRESKIIHVEYYQEGEISegcLLFNKPTHYNNGNYTLIAKNPLGTANQT 390
Cdd:cd05729   24 LECGAGGNPMPNITWLKDGKEFKKEHRIGGTKVEEKGWS---LIIERAIPRDKGKYTCIVENEYGSINHT 90

Immunoglobulin (Ig)-like I-set domain of Neural Cell Adhesion Molecule 1 (NCAM-1); The members here are composed of the fourth Ig domain of Neural Cell Adhesion Molecule 1(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. One of the unique features of I-set domains is the lack of a C" strand. The structures of this group show that the Ig domain lacks this strand and thus is a member of the I-set of Ig domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 992319530 210 PEISVSHVNLTVREGDNAVITCNGSGSPLPDVDWiVTGLQSINTHQTNLNWTNV---HA--INLTLVNVTSEDNGFTLtC 284
Cdd:cd05869    3 PKITYVENQTAMELEEQITLTCEASGDPIPSITW-RTSTRNISSEEKTLDGHIVvrsHArvSSLTLKYIQYTDAGEYL-C 80