Alpha kinase family; The alpha kinase family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional serine/threonine protein kinases. The family contains myosin heavy chain kinases, elongation factor-2 kinases, and bifunctional ion channel kinases. These kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+/Ca2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1383 MTPMVFAKGLADSGCWGDKLFGRLVSEElrGGGYGCGLRKASQAKVIYGLEPIFESGRTCIIKVSSLLVFGPSSETSLVG 1462
Cdd:cd16966      9 MSPLIFAKDLLDSGYWGDKLFGRIATEE--LHFGEGVLRKASRSKVIYGLMPIFKSGHTCIIKVHNAIAYGTRNEDSLIQ 86

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1463 RNYDVTIQGCKIQNMSREYCKIFAAEARAAPGFGEVPEIIPLYLIYRPANNIPYATLEEDLGKPLESYCSREwGCAEAPT 1542
Cdd:cd16966     87 RNYKLTAQECKVQNTAREYAKIFAAEARPLEGFGEVPEIIPLFLIYRPANNIPYATVEEELIGPFVKYSIRD-GKEINFL 165

                          170       180       190       200       210       220       230
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1743668595 1543 ASGsSEAMQKCQTFQHWLYQWTNGSFLVTDLAGVDWKMTDVQIATKLRGYQGLKESCFPALLDRFASSHQCNAYC 1617
Cdd:cd16966    166 RSE-SEAGQKCCTFQHWVYQWTNGCLLVTDLQGVGMKLTDVGIATLAKGYQGLKGNCSMTFIDQFAALHQCNKYC 239

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595  337 QSRRSSENCIPS--SDEPDSCGT------QGPVGVEQVQTQPRGRAARG-PGSSGTDSTRKPASAVGTPDKAQKAPGPGP 407
Cdd:pfam03154  139 QDNRSTSPSIPSpqDNESDSDSSaqqqilQTQPPVLQAQSGAASPPSPPpPGTTQAATAGPTPSAPSVPPQGSPATSQPP 218

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595  408 GQEVYFSLKDMYLENTQAVRPLGEEGPQTLSVRAPGESPKGKAPLRARSEGVPGAPGQPT-HSLTpqpTRPFNRKRFAPP 486
Cdd:pfam03154  219 NQTQSTAAPHTLIQQTPTLHPQRLPSPHPPLQPMTQPPPPSQVSPQPLPQPSLHGQMPPMpHSLQ---TGPSHMQHPVPP 295

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 1743668595  487 KPKGEATTDSK---PISSLSQAPECGAQSLGKAPPQASVQVPTPP 528
Cdd:pfam03154  296 QPFPLTPQSSQsqvPPGPSPAAPGQSQQRIHTPPSQSQLQSQQPP 340

Alpha-kinase domain of alpha-protein kinases 2 and 3; Alpha-protein kinases 2 (ALPK2) and 3 (ALPK3) are also called heart alpha-protein kinase (HAK) and muscle alpha-protein kinase (MAK), respectively. They both contain a C-terminal alpha-kinase domain and two immunoglobulin (Ig)-like domains. Loss of function mutations in ALPK3 can cause early-onset and familial cardiomyopathy in humans. The ALPK2 gene may also be a novel candidate gene for inherited hypertension in Dahl rats. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1383 MTPMVFAKGLADSGCWGDKLFGRLVSEElrGGGYGCGLRKASQAKVIYGLEPIFESGRTCIIKVSSLLVFGPSSETSLVG 1462
Cdd:cd16966      9 MSPLIFAKDLLDSGYWGDKLFGRIATEE--LHFGEGVLRKASRSKVIYGLMPIFKSGHTCIIKVHNAIAYGTRNEDSLIQ 86

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1463 RNYDVTIQGCKIQNMSREYCKIFAAEARAAPGFGEVPEIIPLYLIYRPANNIPYATLEEDLGKPLESYCSREwGCAEAPT 1542
Cdd:cd16966     87 RNYKLTAQECKVQNTAREYAKIFAAEARPLEGFGEVPEIIPLFLIYRPANNIPYATVEEELIGPFVKYSIRD-GKEINFL 165

                          170       180       190       200       210       220       230
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1743668595 1543 ASGsSEAMQKCQTFQHWLYQWTNGSFLVTDLAGVDWKMTDVQIATKLRGYQGLKESCFPALLDRFASSHQCNAYC 1617
Cdd:cd16966    166 RSE-SEAGQKCCTFQHWVYQWTNGCLLVTDLQGVGMKLTDVGIATLAKGYQGLKGNCSMTFIDQFAALHQCNKYC 239

Alpha-kinase family; This family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional kinases. The family contains myosin heavy chain kinases and Elongation Factor-2 kinase and a bifunctional ion channel. This family is known as the alpha-kinase family. The structure of the kinase domain revealed unexpected similarity to eukaryotic protein kinases in the catalytic core as well as to metabolic enzymes with ATP-grasp domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1417 GCG-LRKASQAKViyglEPIFESGRTCIIKVSSLLVfgpssetslVGRNYDVTIQGCKIQNMSREYCKIFAAEARAAPGF 1495
Cdd:pfam02816    1 AEGaMRKAFKAKV----DPGDESGQNYVAKEFKKIV---------YGVELEYYFEDAQSQALAKELAEEFNAEARALENF 67

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1496 GEVP-EIIPLYLI-YRPANNIPYATLEEDLGKPLESYCSRE-WgcaeapTASGSSEAMQKCQTFQHWLYQWTNGSFLVTD 1572
Cdd:pfam02816   68 PPKKiEFIPPYVVeLDPANGKPYYLVEPFLEGNFVKYNSNTgF------VSEEDDELEQTMQAFSHFTYERSGGQLLVCD 141

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 1743668595 1573 LAGVDWKMTDVQIATKLRGYQGLKESCFPAlLDRFASSHQCNAYC 1617
Cdd:pfam02816  142 LQGVGNLLTDPAIHTKDGKRFGDTNLGEEG-IASFFSTHKCNKIC 185

Immunoglobulin I-set domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595   77 PLFETTLKSRSVSEDSDVRFTCIVTGYPEPEVTWYKDDTEL--DRycglpKYEITHQGNRHTLQLYRCREEDAAIYQASA 154
Cdd:pfam07679    1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrsSD-----RFKVTYEGGTYTLTISNVQPDDSGKYTCVA 75

                           90
                   ....*....|....*
gi 1743668595  155 QNSKGIVSCSGVLEV 169
Cdd:pfam07679   76 TNSAGEAEASAELTV 90

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595  337 QSRRSSENCIPS--SDEPDSCGT------QGPVGVEQVQTQPRGRAARG-PGSSGTDSTRKPASAVGTPDKAQKAPGPGP 407
Cdd:pfam03154  139 QDNRSTSPSIPSpqDNESDSDSSaqqqilQTQPPVLQAQSGAASPPSPPpPGTTQAATAGPTPSAPSVPPQGSPATSQPP 218

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595  408 GQEVYFSLKDMYLENTQAVRPLGEEGPQTLSVRAPGESPKGKAPLRARSEGVPGAPGQPT-HSLTpqpTRPFNRKRFAPP 486
Cdd:pfam03154  219 NQTQSTAAPHTLIQQTPTLHPQRLPSPHPPLQPMTQPPPPSQVSPQPLPQPSLHGQMPPMpHSLQ---TGPSHMQHPVPP 295

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 1743668595  487 KPKGEATTDSK---PISSLSQAPECGAQSLGKAPPQASVQVPTPP 528
Cdd:pfam03154  296 QPFPLTPQSSQsqvPPGPSPAAPGQSQQRIHTPPSQSQLQSQQPP 340

Alpha-kinase domain of alpha-protein kinases 2 and 3; Alpha-protein kinases 2 (ALPK2) and 3 (ALPK3) are also called heart alpha-protein kinase (HAK) and muscle alpha-protein kinase (MAK), respectively. They both contain a C-terminal alpha-kinase domain and two immunoglobulin (Ig)-like domains. Loss of function mutations in ALPK3 can cause early-onset and familial cardiomyopathy in humans. The ALPK2 gene may also be a novel candidate gene for inherited hypertension in Dahl rats. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1383 MTPMVFAKGLADSGCWGDKLFGRLVSEElrGGGYGCGLRKASQAKVIYGLEPIFESGRTCIIKVSSLLVFGPSSETSLVG 1462
Cdd:cd16966      9 MSPLIFAKDLLDSGYWGDKLFGRIATEE--LHFGEGVLRKASRSKVIYGLMPIFKSGHTCIIKVHNAIAYGTRNEDSLIQ 86

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1463 RNYDVTIQGCKIQNMSREYCKIFAAEARAAPGFGEVPEIIPLYLIYRPANNIPYATLEEDLGKPLESYCSREwGCAEAPT 1542
Cdd:cd16966     87 RNYKLTAQECKVQNTAREYAKIFAAEARPLEGFGEVPEIIPLFLIYRPANNIPYATVEEELIGPFVKYSIRD-GKEINFL 165

                          170       180       190       200       210       220       230
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1743668595 1543 ASGsSEAMQKCQTFQHWLYQWTNGSFLVTDLAGVDWKMTDVQIATKLRGYQGLKESCFPALLDRFASSHQCNAYC 1617
Cdd:cd16966    166 RSE-SEAGQKCCTFQHWVYQWTNGCLLVTDLQGVGMKLTDVGIATLAKGYQGLKGNCSMTFIDQFAALHQCNKYC 239

Alpha-kinase domain of alpha-protein kinase 2; Alpha-protein kinase 2 (ALPK2) is also called heart alpha-protein kinase (HAK). Little functional information is known about ALPK2. In a three-dimensional colonic-crypt model, it has been identified as crucial for luminal apoptosis and expression of DNA repair-related genes, possibly in the transition of normal colonic crypt to adenoma. The ALPK2 gene may also be a novel candidate gene for inherited hypertension in Dahl rats. ALPK2 contains a C-terminal alpha-kinase domain and two immunoglobulin (Ig)-like domains. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1386 MVFAKGLADSGCWGDKLFGRLVSEELRgggYGCGL-RKASQAKVIYGLEPIFESGRTCIIKVSSLLVFGPSSETSLVGRN 1464
Cdd:cd16974     12 LMFKEDFLSDSYFGGNLHGRIATEKLH---FGEGMhRKAFRSKVMCGLLPVFLPGHACVLKVHNAIAYGTKNNDELIQKN 88

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1465 YDVTIQGCKIQNMSREYCKIFAAEARAAPGFGEVPEIIPLYLIYRPANNIPYATLEEDLGKPLESYCSREwgCAEAPTAS 1544
Cdd:cd16974     89 YKLAVQECYVQNTAREYAKIYAAEAQPLEGFGEVPEIIPIFLIHRPANNIPYATVEEELIGDFVKYSVRD--GKEINVLR 166

                          170       180       190       200       210       220       230
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1743668595 1545 GSSEAMQKCQTFQHWLYQWTNGSFLVTDLAGVDWKMTDVQIATKLRGYQGLKESCFPALLDRFASSHQCNAYC 1617
Cdd:cd16974    167 RDSEAGQKCCTFQHWVYQKTDGNLLVTDMQGVGMKLTDVGIATCSKGYKGFKGNCSVSFIDQFKALHQCNKYC 239

Alpha-kinase family; This family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional kinases. The family contains myosin heavy chain kinases and Elongation Factor-2 kinase and a bifunctional ion channel. This family is known as the alpha-kinase family. The structure of the kinase domain revealed unexpected similarity to eukaryotic protein kinases in the catalytic core as well as to metabolic enzymes with ATP-grasp domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1417 GCG-LRKASQAKViyglEPIFESGRTCIIKVSSLLVfgpssetslVGRNYDVTIQGCKIQNMSREYCKIFAAEARAAPGF 1495
Cdd:pfam02816    1 AEGaMRKAFKAKV----DPGDESGQNYVAKEFKKIV---------YGVELEYYFEDAQSQALAKELAEEFNAEARALENF 67

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1496 GEVP-EIIPLYLI-YRPANNIPYATLEEDLGKPLESYCSRE-WgcaeapTASGSSEAMQKCQTFQHWLYQWTNGSFLVTD 1572
Cdd:pfam02816   68 PPKKiEFIPPYVVeLDPANGKPYYLVEPFLEGNFVKYNSNTgF------VSEEDDELEQTMQAFSHFTYERSGGQLLVCD 141

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 1743668595 1573 LAGVDWKMTDVQIATKLRGYQGLKESCFPAlLDRFASSHQCNAYC 1617
Cdd:pfam02816  142 LQGVGNLLTDPAIHTKDGKRFGDTNLGEEG-IASFFSTHKCNKIC 185

Alpha kinase family; The alpha kinase family is a novel family of eukaryotic protein kinase catalytic domains, which have no detectable similarity to conventional serine/threonine protein kinases. The family contains myosin heavy chain kinases, elongation factor-2 kinases, and bifunctional ion channel kinases. These kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+/Ca2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1418 CGLRKAsqAKVIYGLEpifeSGRTCIIKVSSllvfgpssETSLVGRNYDVTIQGCKIQNMSREYCKIFAAEARAAPGFGE 1497
Cdd:cd04515     33 GAMREA--FKAKDLDS----KGKKYVAKRFK--------RIGDPEENLEDLFDELRMQALAQYLAKEFNARAKSKNLIAP 98

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1498 VPEIIPLYLIYRPANNIP---YATLEEDLGKPLESYCSREwGCAEaptasgSSEAMQKCQTFQHWLYQWTNGSFLVTDLA 1574
Cdd:cd04515     99 KINFVDPFVVKLGDRDDPgkvVFLVEPFLEGKFVKYNNNN-GMVN------DEDLGETAQAFSHFTYERSGGQLLVTDLQ 171

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|...
gi 1743668595 1575 GVDWKMTDVQIATKLRGYQGLKeSCFPALLDRFASSHQCNAYC 1617
Cdd:cd04515    172 GVGLVLTDPQIHTVDGGGFGLG-NLGEEGIKRFFKTHKCNEIC 213

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595    84 KSRSVSEDSDVRFTCIVTGYPEPEVTWYKDDTELDRYCGlpKYEITHQGNRHTLQLYRCREEDAAIYQASAQNSKGIVSC 163
Cdd:smart00410    2 PSVTVKEGESVTLSCEASGSPPPEVTWYKQGGKLLAESG--RFSVSRSGSTSTLTISNVTPEDSGTYTCAATNSSGSASS 79

                    ....*.
gi 1743668595   164 SGVLEV 169
Cdd:smart00410   80 GTTLTV 85

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 1743668595   94 VRFTCIVTGYPEPEVTWYKDDTELDRYcglPKYEITHQGNRHTLQLYRCREEDAAIYQASAQNSKG 159
Cdd:cd00096      1 VTLTCSASGNPPPTITWYKNGKPLPPS---SRDSRRSELGNGTLTISNVTLEDSGTYTCVASNSAG 63

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595   77 PLFETTLKSRSVSEDSDVRFTCIVTGYPEPEVTWYKDDTELDrycGLPKYEITHQGNRHTLQLYRCREEDAAIYQASAQN 156
Cdd:pfam13927    2 PVITVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPIS---SGSTRSRSLSGSNSTLTISNVTRSDAGTYTCVASN 78

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595   82 TLKSRSVSEDSDVRFTCIVTGYPEPEVTWYKDD---TELDRYcglpKYEITHQGNrHTLQLYRCREEDAAIYQASAQNSK 158
Cdd:cd20973      3 TLRDKEVVEGSAARFDCKVEGYPDPEVKWMKDDnpiVESRRF----QIDQDEDGL-CSLIISDVCGDDSGKYTCKAVNSL 77

                           90
                   ....*....|.
gi 1743668595  159 GIVSCSGVLEV 169
Cdd:cd20973     78 GEATCSAELTV 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 1743668595   84 KSRSVSEDSDVRFTCIVTGYPEPEVTWYKDDTELDRycglPKYEITHQgnrHTLQLYRCREEDAAIYQASAQNSKGIVSC 163
Cdd:cd05725      5 QNQVVLVDDSAEFQCEVGGDPVPTVRWRKEDGELPK----GRYEILDD---HSLKIRKVTAGDMGSYTCVAENMVGKIEA 77

                   ....*.
gi 1743668595  164 SGVLEV 169
Cdd:cd05725     78 SATLTV 83

Alpha-kinase domain of myosin heavy chain kinase and similar domains; This group is composed of alpha-kinase domains of Dictyostelium discoideum myosin heavy chain kinases A-D (MHCKA, MHCKB, MHCKC, MHCKD), alpha-protein kinase 1 (AK1), and similar proteins. The myosin heavy chain kinases are involved in regulating myosin II filament assembly in Dictyostelium discoideum. They phosphorylate target threonine residues located in the carboxyl-terminal portion of the myosin II heavy chain (MHC) tail, resulting in filament disassembly. The different MHCK isoforms display different spatial regulation, indicating specific roles for each isoform in fine tuning the Dictyostelium actomyosin cytoskeleton. They all contain an alpha-kinase domain as well as WD40 repeats at the C-terminus. AK1 contains an N-terminal Arf-GAP domain and a central alpha-kinase domain. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1743668595 1554 QTFQHWLYQWTNGSFLVTDLAGVDWKMTDVQIATKL-----RGYQGLKEscfpalLDRFASSHQCNAYC 1617
Cdd:cd16968    140 QAFSHFTYEASGHQLLVVDIQGVGDLYTDPQIHTIDgkgfgKGNLGQKG------IEKFLETHKCNAIC 202

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        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1743668595   87 SVSEDSDVRFTCIVTGYPEPEVTWYKDDTELDRYCglpKYEITHQGNRHTLQLYRCREEDAAIYQASAQNSKGIVS 162
Cdd:cd20949     10 TVKEGQSATILCEVKGEPQPNVTWHFNGQPISASV---ADMSKYRILADGLLINKVTQDDTGEYTCRAYQVNSIAS 82

First Ig-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the first 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 1743668595   77 PLFETTLKSRSVSEDSDVRFTCIVTGYPEPEVTWYKDDTELDrYCGLPKYEITHQGNRHTLQLYRCREEDAAIYQASAQN 156
Cdd:cd20974      1 PVFTQPLQSVVVLEGSTATFEAHVSGKPVPEVSWFRDGQVIS-TSTLPGVQISFSDGRAKLSIPAVTKANSGRYSLTATN 79

                   ...
gi 1743668595  157 SKG 159
Cdd:cd20974     80 GSG 82

First immunoglobulin (Ig)-like domain of neural cell adhesion molecule NCAM-2; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the first immunoglobulin (Ig)-like domain of neural cell adhesion molecule NCAM-2 (OCAM/mamFas II, RNCAM). NCAM-2 is organized similarly to NCAM-1, including five N-terminal Ig-like domains and two fibronectin type III domains. NCAM-2 is differentially expressed in the developing and mature olfactory epithelium (OE), and may function like NCAM, as an adhesion molecule. 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 1743668595   96 FTCIVTGYPEpEVTWYKDDTEldRYCGLPKYEITHQGNRHTLQLYRCREEDAAIYQASAQNSKG 159
Cdd:cd05866     20 FTCTAIGEPE-SIDWYNPQGE--KIVSSQRVVVQKEGVRSRLTIYNANIEDAGIYRCQATDAKG 80

Alpha-kinase domain of channel kinase 2, also called transient receptor potential cation channel subfamily M member 6; Channel kinase 2 (ChaK2), also called transient receptor potential cation channel subfamily M member 6 (TRMP6) or melastatin-related TRP cation channel 6, is a fusion protein containing a transmembrane ion pore or channel and a C-terminal alpha-kinase domain, both of which are functional. It is highly expressed in the kidney and instestine. It is a cation-selective channel that preferentially permeates Zn2+, Mg2+, and Ca2+ ions. It is a central regulator of Mg2+ and Ca2+ homeostasis. TRPM6 is considered to be the Mg2+ entry pathway in the distal convoluted tubule of the kidney, where it functions as a gatekeeper for controlling the body's Mg2+ balance. Mutations in the TRPM6 gene cause the autosomal recessive disorder hypomagnesemia with secondary hypocalcemia, which often results in severe muscular and neurologic complications from early infancy that can lead to neurologic damage or cardiac arrest if left untreated. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1406 LVSEELRGGgygcgLRKASQAKVIYGLEPIFESGRTCIIKVssllvFGPSsetslVGRNYDVTIQGCKIQNMS-REYCKI 1484
Cdd:cd16972     35 LSREEMDGG-----LRRAMKVVCTWSEDDVLKPGQVFIVKS-----FLPE-----VVQTWQKIFNNSTVLHLClREIQQQ 99

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1485 FAAEaRAAPGFGEV-PEIIP-------LYLIYRPANNiPYATLEEDLGKPLESYCSREwGCAEAPTaSGSSEAMQkcqTF 1556
Cdd:cd16972    100 RAAQ-KLIYTFNQVkPHSIPytprfleVFLIYCHSAN-QWLTIEKYLTGEFRKYNNNN-GDEITPT-SLLEETLL---AF 172

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1743668595 1557 QHWLYQWTNGSFLVTDLAGVDWKMTDVQIaTKLRGYQGLKESCFPALLDR-----FASSHQCNAYC 1617
Cdd:cd16972    173 SHWTYEYTRGELLVLDLQGVGENLTDPSV-IKPEDKQSRGMVFGPANLGEdairnFIAKHHCNSCC 237

Fourth immunoglobulin (Ig)-like domain of platelet-derived growth factor receptor (PDGFR); The members here are composed of the fourth immunoglobulin (Ig)-like domain of platelet-derived growth factor receptor (PDGFR; also known as cluster of differentiation (CD) 140a) alpha and beta. PDGF is a potent mitogen for connective tissue cells. PDGF-stimulated processes are mediated by three different PDGFs (PDGF-A,PDGF-B, and PDGF-C). PDGFR alpha binds to all three PDGFs, whereas the PDGFR beta binds only to PDGF-B. PDGF alpha is organized as an extracellular component having five Ig-like domains, a transmembrane segment, and a cytoplasmic portion having protein tyrosine kinase activity. In mice, PDGFR alpha and PDGFR beta are essential for normal development.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595   94 VRFTCIVTGYPEPEVTWYKDDTELdrycGLPKYEITHQGNR-------HTLQLYRCREEDAAIYQASAQNSKGIVSCSGV 166
Cdd:cd05859     21 KEFVVEVEAYPPPQIRWLKDNRTL----IENLTEITTSTRNvqetryvSKLKLIRAKEEDSGLYTALAQNEDAVKSYTFA 96

                   ...
gi 1743668595  167 LEV 169
Cdd:cd05859     97 LQI 99

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595   76 QPLFETTLKSRSVsedsdvRFTCIVTGYPEPEVTWYKDdteldrycGLPKYEITHQGNRHTLQLYRCREEDAAIYQASAQ 155
Cdd:cd04976      9 QQVLEATAGKRSV------RLPMKVKAYPPPEVVWYKD--------GLPLTEKARYLTRHSLIIKEVTEEDTGNYTILLS 74

                   ..
gi 1743668595  156 NS 157
Cdd:cd04976     75 NK 76

Immunoglobulin (Ig)-like domain of the human basement membrane heparan sulfate proteoglycan perlecan and similar proteins; The members here are composed of the immunoglobulin (Ig)-like domain of the human basement membrane heparan sulfate proteoglycan perlecan, also known as HSPG2, and similar proteins. Perlecan consists of five domains: domain I has three putative heparan sulfate attachment sites, domain II has four LDL receptor-like repeats, and one Ig-like repeat, domain III resembles the short arm of laminin chains, domain IV has multiple Ig-like repeats (21 repeats in human perlecan), and domain V resembles the globular G domain of the laminin A chain and internal repeats of EGF. Perlecan may participate in a variety of biological functions including cell binding, LDL-metabolism, basement membrane assembly and selective permeability, calcium binding, and growth- and neurite-promoting activities.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1743668595   94 VRFTCIVTGYPEPEVTWYKDdteLDRYCGLPKYEITHQGNRHTLQLYRCREEDAAIYQASAQNSKGIV 161
Cdd:cd05743      4 VEFTCVATGVPTPIINWRLN---WGHVPDSARVSITSEGGYGTLTIRDVKESDQGAYTCEAINTRGMV 68

Alpha-kinase domain of channel kinases; This group is composed of channel kinases 1 (ChaK1) and 2 (ChaK2), and similar proteins. ChaK1 and ChaK2 are also called transient receptor potential cation channel subfamily M members 7 (TRMP7) and 6 (TRMP6), respectively. They are fusion proteins containing a transmembrane ion pore or channel and a C-terminal alpha-kinase domain, both of which are functional. They are both cation-selective channels that preferentially permeate Zn2+, Mg2+, and Ca2+ ions. They are central regulators of Mg2+ and Ca2+ homeostasis. TRMP7 is ubiquitously expressed while TRMP6 is highly expressed in specific tissues such as the kidney and intestine. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1406 LVSEELRGGgygcgLRKASQAKVIYGLEPIFESGRTCIIKVssllvFGPSsetslVGRNYDVTIQgckiQNMSREYCKIF 1485
Cdd:cd16965     35 LSQEEMDGG-----LRRATKVVCTWSEGDILKLGSVYIVKS-----FLPE-----VVRTWQKIFP----ESTVLHLCLRE 95

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1486 AAEARAAP----GFGEV-PEIIP-------LYLIY-RPANNipYATLEEDLGKPLESYCSREwGCAEAPTaSGSSEAMQk 1552
Cdd:cd16965     96 IQQQRAAQklmqRFNQVkPSSIPysprfleVFLLYcHSAGQ--WLTVENNMTGEFRKYNNNN-GDEILPT-NTLEETML- 170

                          170       180       190       200       210       220       230
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1743668595 1553 cqTFQHWLYQWTNGSFLVTDLAGVDWKMTDVQIaTKLRGYQGLKESCFPALL-----DRFASSHQCNAYC 1617
Cdd:cd16965    171 --AFSHWTYEYTRGELLVLDLQGVGENLTDPSV-IKVEDKSSGEMVFGPANLgedaiQNFVAKHHCNSCC 237

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 1743668595   88 VSEDSDVRFTCIVTGYPEPEVTWYKDDTELdrycgLPKYEITHQGNRHTLQLYRCREEDAAIYQASAQNSKGIVSCSGVL 167
Cdd:cd20952     11 VAVGGTVVLNCQATGEPVPTISWLKDGVPL-----LGKDERITTLENGSLQIKGAEKSDTGEYTCVALNLSGEATWSAVL 85

                   ..
gi 1743668595  168 EV 169
Cdd:cd20952     86 DV 87

Alpha-kinase domain of channel kinase 1, also called transient receptor potential cation channel subfamily M member 7; Channel kinase 1 (ChaK1), also called transient receptor potential cation channel subfamily M member 7 (TRMP7) or long transient receptor potential channel 7 (LTrpC7), is a fusion protein containing a transmembrane ion pore or channel and a C-terminal alpha-kinase domain, both of which are functional. It is ubiquitously expressed and is a cation-selective channel that preferentially permeates Zn2+, Mg2+, and Ca2+ ions. It is a central regulator of Mg2+ and Ca2+ homeostasis. TRPM7 plays a role in cancer proliferation, stroke, hydrogen peroxide dependent neurodegeneration, and heavy metal toxicity. Alpha-kinase is an atypical protein kinase catalytic domain with no detectable similarity to conventional protein serine/threonine kinases. The alpha-kinase family was named after the unique mode of substrate recognition by its initial members, the Dictyostelium heavy chain kinases, which targeted protein sequences that adopt an alpha-helical conformation. More recently, alpha-kinases were found to also target residues in non-helical regions.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1743668595 1556 FQHWLYQWTNGSFLVTDLAGVDWKMTDVQIATKlrGYQGLKESCF-PALL-----DRFASSHQCNAYC 1617
Cdd:cd16971    172 FSHWTYEYTRGELLVLDLQGVGENLTDPSVIKA--GEKRSYDMVFgPANLgedaiKNFRAKHHCNSCC 237