PDZ domain of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2, SHANK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SHANK1, SHANK2, SHANK3, and related domains. SHANK family proteins, SHANK1 (also known as somatostatin receptor-interacting protein, SSTR-interacting protein, SSTRIP), SHANK2 (also known as cortactin-binding protein 1, proline-rich synapse-associated protein 1), and SHANK3 (proline-rich synapse-associated protein 2) are synaptic scaffolding proteins which are highly enriched in the post-synaptic densities of excitatory synapses. They have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling, and are regulators of Cav1 calcium current and CREB target expression. Many protein ligands have been identified for the Shank PDZ domain, such as GKAP (also known as SAPAP), betaPIX (a guanine nucleotide exchange factor used by Rho GTPase family members Rac1 and Cdc42), alpha-latrotoxin, neuroligin, group I metabotropic glutamate receptors (mGluRs), and L-type calcium channels. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SHANK-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  592 DYVIEEKSATLQKRDsEGFGFVLRGAKAETPIEEFTPTPAFPALQYLESVDLEGVAWRAGLRTGDFLIEVNGVSVVKVGH 671
Cdd:cd06746     1 DSIIDPRTVVLQKGD-KGFGFVLRGAKAVGPILEFTPTPAFPALQYLESVDPGGVADKAGLKKGDFLLEINGEDVVKASH 79

                          90       100
                  ....*....|....*....|..
gi 688547127  672 RQVVSLIRQGGSRLVMKVVSVT 693
Cdd:cd06746    80 EQVVNLIRQSGNTLVLKVVTVT 101

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 688547127 1576 PLALWSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLAELGVTRVGHRMNIERALKQLL 1641
Cdd:cd09506     1 PVHEWTVDDVGDWLESLNLGEHRERFMDNEIDGSHLPNLDKEDLTELGVTRVGHRMNIERALKKLL 66

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688547127  502 RTFIAINSHTPQGEGEITLNRGERVKVLSIGEGGFWEGSVKGRTGWFPAHCV 553
Cdd:cd11984     1 RTFIAVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

PDZ domain of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2, SHANK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SHANK1, SHANK2, SHANK3, and related domains. SHANK family proteins, SHANK1 (also known as somatostatin receptor-interacting protein, SSTR-interacting protein, SSTRIP), SHANK2 (also known as cortactin-binding protein 1, proline-rich synapse-associated protein 1), and SHANK3 (proline-rich synapse-associated protein 2) are synaptic scaffolding proteins which are highly enriched in the post-synaptic densities of excitatory synapses. They have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling, and are regulators of Cav1 calcium current and CREB target expression. Many protein ligands have been identified for the Shank PDZ domain, such as GKAP (also known as SAPAP), betaPIX (a guanine nucleotide exchange factor used by Rho GTPase family members Rac1 and Cdc42), alpha-latrotoxin, neuroligin, group I metabotropic glutamate receptors (mGluRs), and L-type calcium channels. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SHANK-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  592 DYVIEEKSATLQKRDsEGFGFVLRGAKAETPIEEFTPTPAFPALQYLESVDLEGVAWRAGLRTGDFLIEVNGVSVVKVGH 671
Cdd:cd06746     1 DSIIDPRTVVLQKGD-KGFGFVLRGAKAVGPILEFTPTPAFPALQYLESVDPGGVADKAGLKKGDFLLEINGEDVVKASH 79

                          90       100
                  ....*....|....*....|..
gi 688547127  672 RQVVSLIRQGGSRLVMKVVSVT 693
Cdd:cd06746    80 EQVVNLIRQSGNTLVLKVVTVT 101

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 688547127 1576 PLALWSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLAELGVTRVGHRMNIERALKQLL 1641
Cdd:cd09506     1 PVHEWTVDDVGDWLESLNLGEHRERFMDNEIDGSHLPNLDKEDLTELGVTRVGHRMNIERALKKLL 66

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 3; Shank3, also called ProSAP2 (Proline-rich synapse-associated protein 2), is widely expressed. It plays a role in the formation of dendritic spines and synapses. Haploinsufficiency of the Shank3 gene causes the 22q13 deletion/Phelan-McDermid syndrome, and variants of Shank3 have been implicated in autism spectrum disorder, schizophrenia, and intellectual disability. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688547127  502 RTFIAINSHTPQGEGEITLNRGERVKVLSIGEGGFWEGSVKGRTGWFPAHCV 553
Cdd:cd11984     1 RTFIAVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 688547127   1580 WSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTK-DDLAELGVTRVGHRMNIERALKQLLES 1643
Cdd:smart00454    4 WSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTSeEDLKELGITKLGHRKKILKAIQKLKEQ 68

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127   299 IHQACRHGNVQHLEHLLFYGAEMSAQNASGNTALHLCALYNQEGCARVLLfRGANKEIKNyNNQTAFQVAIIAGNFDLAE 378
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLL-EHADVNLKD-NGRTALHYAARSGHLEIVK 78

                           90
                   ....*....|
gi 688547127   379 IIkIHKTSDV 388
Cdd:pfam12796   79 LL-LEKGADI 87

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*.
gi 688547127    500 PGRTFIAINSHTPQGEGEITLNRGERVKVLSIGEGGFWEGSVK-GRTGWFPAHCVE 554
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGrGKEGLFPSNYVE 56

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  926 PVEPTPITRPQTPTSGPVPPERGRRRGPPvenPYANVGRlsavyTPTKPqrRKSPLVKQGPVEEGAAAHSSrDPSPLGGS 1005
Cdd:PHA03247 2564 PDRSVPPPRPAPRPSEPAVTSRARRPDAP---PQSARPR-----APVDD--RGDPRGPAPPSPLPPDTHAP-DPPPPSPS 2632

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127 1006 RIPHSSRAEQFQQQVLSERARITPPGARRRPSVFLSVEGGATEPQTTP-------LLSQSHSVDELAELPPPAPMLSPGP 1078
Cdd:PHA03247 2633 PAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRLGRAAQASSPPqrprrraARPTVGSLTSLADPPPPPPTPEPAP 2712

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127 1079 PPGGTTFIHPLTGRPLDPSSPLALALAARERALSGrntptptpspTPSPTQGRAVERPETEGGATPPAPLEAPPSNSWRD 1158
Cdd:PHA03247 2713 HALVSATPLPPGPAAARQASPALPAAPAPPAVPAG----------PATPGGPARPARPPTTAGPPAPAPPAAPAAGPPRR 2782

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688547127 1159 EPVSITETASQVTSGSPGSGRSLEEALAPPGVQNIQPALMD---TEHTPPAVPPTLPSPAP 1216
Cdd:PHA03247 2783 LTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASpagPLPPPTSAQPTAPPPPP 2843

C-terminal processing protease CtpA/Prc, contains a PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  585 DNYTSYSDYVIEEKSATLQKRDSEGFGFVLR----GAKAETPIEEftpTPAfpalqylesvdlegvaWRAGLRTGDFLIE 660
Cdd:COG0793    37 DPHSYYLDPEEYEDFQESTSGEFGGLGAELGeedgKVVVVSVIPG---SPA----------------EKAGIKPGDIILA 97

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688547127  661 VNGVSVVKVGHRQVVSLIR-QGGSRLVMKVVSV-TRKPDTGDVVRKKAPPPP 710
Cdd:COG0793    98 IDGKSVAGLTLDDAVKLLRgKAGTKVTLTIKRPgEGEPITVTLTRAEIKLPS 149

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 688547127   888 QSRSSFRPGAEPKIHGPVTTDRQRKTRSMIILQDTS----HLPVEPTP---------ITRPQTPTSGPVPPERGRRRGPP 954
Cdd:pfam03154  232 QQTPTLHPQRLPSPHPPLQPMTQPPPPSQVSPQPLPqpslHGQMPPMPhslqtgpshMQHPVPPQPFPLTPQSSQSQVPP 311

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127   955 VENPYANVGRLSAVYTP---TKPQRRKSPLVKQGPVEEGAAAHS--------SRDPSPLGGSRIPHSSRAEQFQQ----- 1018
Cdd:pfam03154  312 GPSPAAPGQSQQRIHTPpsqSQLQSQQPPREQPLPPAPLSMPHIkpppttpiPQLPNPQSHKHPPHLSGPSPFQMnsnlp 391

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  1019 -----QVLSERARITPPGARRRPSVFLS-VEGGATEPQTTPLLSQSHSVDELAELPPPAPMLSPGPP----------PGG 1082
Cdd:pfam03154  392 pppalKPLSSLSTHHPPSAHPPPLQLMPqSQQLPPPPAQPPVLTQSQSLPPPAASHPPTSGLHQVPSqspfpqhpfvPGG 471

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  1083 TTFIHPLTGRPLDPSSPLALALAARERALSGRNTPTPTPSPTPSPTQGRAVERPETEGGATPPAPLEAP-PSNSWRDEPV 1161
Cdd:pfam03154  472 PPPITPPSGPPTSTSSAMPGIQPPSSASVSSSGPVPAAVSCPLPPVQIKEEALDEAEEPESPPPPPRSPsPEPTVVNTPS 551

                   ....*.
gi 688547127  1162 SITETA 1167
Cdd:pfam03154  552 HASQSA 557

PDZ domain of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2, SHANK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SHANK1, SHANK2, SHANK3, and related domains. SHANK family proteins, SHANK1 (also known as somatostatin receptor-interacting protein, SSTR-interacting protein, SSTRIP), SHANK2 (also known as cortactin-binding protein 1, proline-rich synapse-associated protein 1), and SHANK3 (proline-rich synapse-associated protein 2) are synaptic scaffolding proteins which are highly enriched in the post-synaptic densities of excitatory synapses. They have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling, and are regulators of Cav1 calcium current and CREB target expression. Many protein ligands have been identified for the Shank PDZ domain, such as GKAP (also known as SAPAP), betaPIX (a guanine nucleotide exchange factor used by Rho GTPase family members Rac1 and Cdc42), alpha-latrotoxin, neuroligin, group I metabotropic glutamate receptors (mGluRs), and L-type calcium channels. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SHANK-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  592 DYVIEEKSATLQKRDsEGFGFVLRGAKAETPIEEFTPTPAFPALQYLESVDLEGVAWRAGLRTGDFLIEVNGVSVVKVGH 671
Cdd:cd06746     1 DSIIDPRTVVLQKGD-KGFGFVLRGAKAVGPILEFTPTPAFPALQYLESVDPGGVADKAGLKKGDFLLEINGEDVVKASH 79

                          90       100
                  ....*....|....*....|..
gi 688547127  672 RQVVSLIRQGGSRLVMKVVSVT 693
Cdd:cd06746    80 EQVVNLIRQSGNTLVLKVVTVT 101

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains proteins, SHANK1, SHANK2, and SHANK3; SHANK proteins (SHANK1, SHANK2, and SHANK3) are core components of the postsynaptic density (PSD) of excitatory synapses. They act as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. They play important roles in proper excitatory synapse and circuit function. Mutations in SHANK genes, especially in SHANK3 and SHANK2, may lead to neuropsychiatric disorders, such as autism spectrum disorder (ASD). SHANK proteins contain an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127   54 VVIRIGIPDLQQTKCLRLDLEAPVWVCKQRVLVTLTQSLTDVLNYGLYLPAFNGRAGKFLDEERLLREYPLPtvTPVPYL 133
Cdd:cd17091     1 IVLRISIPDLNLQKCLKFNPDDTVWDAKQQVLEKLAKDLKDALNYGLFLPPTNGKAGKFLDEERLLREYPLD--GPVGYL 78

                  ....*.
gi 688547127  134 EFRYKR 139
Cdd:cd17091    79 EFKYKR 84

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 1 (SHANK1); SHANK1, also termed somatostatin receptor-interacting protein, or SSTR-interacting protein (SSTRIP), is a postsynaptic density (PSD)-associated scaffolding proteins at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. Mutations in the SHANK1 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation. SHANK1 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127   54 VVIRIGIPDLQQTKCLRLDLEAPVWVCKQRVLVTLTQSLTDVLNYGLYLPAFNGRAGKFLDEERLLREYPLPTVTPVPYL 133
Cdd:cd17175     4 MVFRIGIPDLHQTKCLRFNPDATIWVAKQQVLCTLNESLKDVLNYGLFQPATNGRDAKFLEEERLLREYPQSFEKGVPYL 83

                  ....*
gi 688547127  134 EFRYK 138
Cdd:cd17175    84 EFRYK 88

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  180 LEKGLDPNFHDSDSGESPLTLVAQLDTCADLIKVLRSGGAHLDFRTRDGLTALHKAAQTHNHVALTTLLDLGASPDYKDS 259
Cdd:COG0666    39 LLLLALLALALADALGALLLLAAALAGDLLVALLLLAAGADINAKDDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDK 118

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  260 RGLTPLYHSAMvGGDPYCCELLLYDHAQLGYSDENGWQEIHQACRHGNVQHLEHLLFYGAEMSAQNASGNTALHLCALYN 339
Cdd:COG0666   119 DGETPLHLAAY-NGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENG 197

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*
gi 688547127  340 QEGCARVLLFRGANKEIKNYNNQTAFQVAIIAGNFDLAEIIKIHK 384
Cdd:COG0666   198 HLEIVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAG 242

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 3; Shank3, also called ProSAP2 (Proline-rich synapse-associated protein 2), is widely expressed. It plays a role in the formation of dendritic spines and synapses. Haploinsufficiency of the Shank3 gene causes the 22q13 deletion/Phelan-McDermid syndrome, and variants of Shank3 have been implicated in autism spectrum disorder, schizophrenia, and intellectual disability. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688547127  502 RTFIAINSHTPQGEGEITLNRGERVKVLSIGEGGFWEGSVKGRTGWFPAHCV 553
Cdd:cd11984     1 RTFIAVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 1; Shank1, also called SSTRIP (Somatostatin receptor-interacting protein), is a brain-specific protein that plays a role in the construction of postsynaptic density (PSD) and the maturation of dendritic spines. Mice deficient in Shank1 show altered PSD composition, thinner PSDs, smaller dendritic spines, and weaker basal synaptic transmission, although synaptic plasticity is normal. They show increased anxiety and impaired fear memory, but also show better spatial learning. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 688547127  502 RTFIAINSHTPQGEGEITLNRGERVKVLSIGEGGFWEGSVKGRTGWFPAHCV 553
Cdd:cd11982     1 RTFMAVKPYQSQAEGEISLSKGEKIKVLSVGEGGFWEGQVKGRVGWFPSDCV 52

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688547127  1580 WSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLAELGVTRVGHRMNIERALKQL 1640
Cdd:pfam00536    3 WSVEDVGEWLESIGLGQYIDSFRAGYIDGDALLQLTEDDLLKLGVTLLGHRKKILYAIQRL 63

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  209 DLIKVLRSGGAHLDFRTRDGLTALHKAAQTHNHVALTTLLDLGASPDYKDSRGLTPLYHSAMVGGDPYCCELLLYDHAQL 288
Cdd:COG0666     1 LLLLLLLLLLLLAALLLLLLLALLLLAAALLLLLLLLLLLLLALLALALADALGALLLLAAALAGDLLVALLLLAAGADI 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  289 GYSDENGWQEIHQACRHGNVQHLEHLLFYGAEMSAQNASGNTALHLCALYNQEGCARVLLFRGANKEIKNYNNQTAFQVA 368
Cdd:COG0666    81 NAKDDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLA 160

                         170
                  ....*....|.
gi 688547127  369 IIAGNFDLAEI 379
Cdd:COG0666   161 AANGNLEIVKL 171

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SNX27-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  604 KRDSEGFGFVLRGAKAETPIEEFTPTPAFPALQYLESVDLEGVAWRAGLRTGDFLIEVNGVSVVKVGHRQVVSLIRQGGS 683
Cdd:cd23070     6 VKSETGFGFNVRGQVSEGGQLRSINGELYAPLQHVSAVLEGGAADKAGVRKGDRILEVNGVNVEGATHKQVVDLIKSGGD 85

                  ....*...
gi 688547127  684 RLVMKVVS 691
Cdd:cd23070    86 ELTLTVIS 93

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 688547127   1580 WSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTK-DDLAELGVTRVGHRMNIERALKQLLES 1643
Cdd:smart00454    4 WSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTSeEDLKELGITKLGHRKKILKAIQKLKEQ 68

PDZ domain of tamalin, cytohesin-1-interacting protein (CYTIP), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of tamalin, cytohesin-1-interacting protein, and related domains. Tamalin (trafficking regulator and scaffold protein tamalin, also known as general receptor for phosphoinositides 1-associated scaffold protein, GRASP) functions to link receptors, including group 1 metabotropic glutamate receptors (mGluRs), to neuronal proteins. The tamalin PDZ domain binds the C-terminal domains of group I mGluRs; it also binds potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2), neurotrophin-3 (NT3) TrkCT1-truncated receptor, SAP90/PSD-95-associated protein, and tamalin itself. CYTIP (cytohesin-1-interacting protein, also known as Pleckstrin homology Sec7 and coiled-coil domain-binding protein) sequesters cytohesin-1 in the cytoplasm, limiting its interaction with beta2 integrins; cytohesin-1 binds the CYTIP coiled coil domain. The CYTIP PDZ domain can bind the C-terminal peptide of protocadherin alpha-1 (PCDHA1), indicating a possible interaction between the two. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This tamalin-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  598 KSATLQKRDSEGFGFVLR----GAKAETPIEEFTptpafpalqYLESVDLEGVAWRAGLRTGDFLIEVNGVSVVKVGHRQ 673
Cdd:cd06713     4 RTIILEKQDNETFGFEIQtyglHHKNSNEVEMCT---------YVCRVHEDSPAYLAGLTAGDVILSVNGVSVEGASHQE 74

                          90
                  ....*....|....*..
gi 688547127  674 VVSLIRQGGSRLVMKVV 690
Cdd:cd06713    75 IVELIRSSGNTLRLETL 91

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127   299 IHQACRHGNVQHLEHLLFYGAEMSAQNASGNTALHLCALYNQEGCARVLLfRGANKEIKNyNNQTAFQVAIIAGNFDLAE 378
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLL-EHADVNLKD-NGRTALHYAARSGHLEIVK 78

                           90
                   ....*....|
gi 688547127   379 IIkIHKTSDV 388
Cdd:pfam12796   79 LL-LEKGADI 87

SAM domain of Ste11_fungal subfamily; SAM (sterile alpha motif) domain of Ste11 subfamily is a protein-protein interaction domain. Proteins of this subfamily have SAM domain at the N-terminus and protein kinase domain at the C-terminus. They participate in regulation of mating pheromone response, invasive growth and high osmolarity growth response. MAP triple kinase Ste11 from S.cerevisia is known to interact with Ste20 kinase and Ste50 regulator. These kinases are able to form homodimers interacting through their SAM domains as well as heterodimers or heterogenous complexes when either SAM domain of monomeric or homodimeric form of Ste11 interacts with Ste50 regulator.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 688547127 1580 WSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLAELGVTRVGHRMNIERALKQL 1640
Cdd:cd09534     1 WDEEFVEEWLNELNCGQYLDIFEKNLITGDLLLELDKEALKELGITKVGDRIRLLRAIKSL 61

SAM domain of WDSUB1 proteins; SAM (sterile alpha motif) domain of WDSUB1 subfamily proteins is a putative protein-protein interaction domain. Proteins of this group contain multiple domains: SAM, one or more WD40 repeats and U-box (derived version of the RING-finger domain). Apparently the WDSUB1 subfamily proteins participate in protein degradation through ubiquitination, since U-box domain are known as a member of E3 ubiquitin ligase family, while SAM and WD40 domains most probably are responsible for an E2 ubiquitin-conjugating enzyme binding and a target protein binding.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 688547127 1580 WSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLA-ELGVTRVGHRMNIERALKQL 1640
Cdd:cd09505     5 WSEEDVCTWLRSIGLEQYVEVFRANNIDGKELLNLTKESLSkDLKIESLGHRNKILRKIEEL 66

PDZ domain 2 of delphilin (L-delphilin isoform), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of delphilin (also known as glutamate receptor, ionotropic, delta 2-interacting protein 1, L-delphilin). Delphilin, a postsynaptic protein which it is selectively expressed at cerebellar Purkinje cells, links the glutamate receptor delta 2 subunit (GluRdelta2) with the actin cytoskeleton and various signaling molecules. Two alternatively spliced isoforms of delphilin have been characterized: L-delphilin has two PDZ domains, PDZ1 and PDZ2, and S-delphilin has a single PDZ domain (PDZ2). These two isoforms are differently palmitoylated and may be involved in controlling GluRdelta2 signaling in Purkinje cells. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This delphilin-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  603 QKRDSEGFGFVLRGakaETPIeeftptpafpalqYLESVDLEGVAWRAGLRTGDFLIEVNGVSVVKVGHRQVVSLIRQGG 682
Cdd:cd06744     4 VYRGNGSFGFTLRG---HAPV-------------YIESVDPGSAAERAGLKPGDRILFLNGLDVRNCSHDKVVSLLQGSG 67

                  .
gi 688547127  683 S 683
Cdd:cd06744    68 S 68

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127   232 LHKAAQTHNHVALTTLLDLGASPDYKDSRGLTPLYHSAMvGGDPYCCELLLyDHAQLGySDENGWQEIHQACRHGNVQHL 311
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAK-NGHLEIVKLLL-EHADVN-LKDNGRTALHYAARSGHLEIV 77

                           90
                   ....*....|....
gi 688547127   312 EHLLFYGAEMSAQN 325
Cdd:pfam12796   78 KLLLEKGADINVKD 91

SAM domain of diacylglycerol kinase eta; SAM (sterile alpha motif) domain of DGK-eta subfamily proteins is a protein-protein interaction domain. Proteins of this subfamily are multidomain diacylglycerol kinases. The SAM domain is located at the C-terminus of two out of three isoforms of DGK-eta protein. DGK-eta proteins participate in signal transduction. They regulate the level of second messengers such as diacylglycerol and phosphatidic acid. The SAM domain of DCK-eta proteins can form high molecular weight homooligomers through head-to-tail interactions as well as heterooligomers with the SAM domain of DGK-delta proteins. The oligomerization plays a role in the regulation of the DGK-delta intracellular localization: it is responsible for sustained endosomal localization of the protein and resulted in negative regulation of DCK-eta catalytic activity.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 688547127 1576 PLALWSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLAELGVTRVGHRMNIERALKQL 1640
Cdd:cd09576     1 PVQKWGTDEVAAWLDLLSLGEYKEIFIRHDIRGSELLHLERRDLKDLGIPKVGHMKRILQGIKEL 65

SAM domain of SAM_Neurabin-like subfamily; SAM (sterile alpha motif) domain of Neurabin-like (Neural actin-binding) subfamily is a putative protein-protein interaction domain. This group currently includes the SAM domains of neurobin-I, SAMD14 and neurobin-I/SAMD14-like proteins. Most are multidomain proteins and in addition to SAM domain they contain other protein-binding domains such as PDZ and actin-binding domains. Members of this subfamily participate in signal transduction. Neurabin-I is involved in the regulation of Ca signaling intensity in alpha-adrenergic receptors; it forms a functional pair of opposing regulators with neurabin-II. Neurabins are expressed almost exclusively in neuronal cells. They are known to interact with protein phosphatase 1 and inhibit its activity; they also can bind actin filaments; however, the exact role of the SAM domain is unclear, since SAM doesn't participate in these interactions.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 688547127 1575 RPLALWSKYDVGEWLESVGLGEHRARFLEHEIEGAHLPALTKDDLAELGVTRVGHRMNIERALKQL 1640
Cdd:cd09512     2 RPVSEWSVQQVCQWLMGLGLEQYIPEFTANNIDGQQLLQLDSSKLKALGITSSSDRSLLKKKLKEL 67

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 688547127  506 AINSHTPQGEGEITLNRGERVKVLSIGEGGFWEGSVKGRTGWFPAHCVEE 555
Cdd:cd11877     4 AKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLNGKTGWFPSNYVKE 53

PDZ domain 5 of membrane-associated guanylate kinase inverted 1 (MAGI-1), MAGI-2, and MAGI-3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 5 of MAGI1, 2, 3 (MAGI is also known as Membrane-associated guanylate kinase, WW and PDZ domain-containing protein) and related domains. MAGI proteins have been implicated in the control of cell migration and invasion through altering the activity of phosphatase and tensin homolog (PTEN) and modulating Akt signaling. Four MAGI proteins have been identified (MAGI1-3 and MAGIX). MAGI1-3 have 6 PDZ domains and bind to the C-terminus of PTEN via their PDZ2 domain. MAGIX has a single PDZ domain that is related to MAGI1-3 PDZ domain 5, and belongs to this MAGI1,2,3-like family. Other binding partners for MAGI1 include JAM4, C-terminal tail of high risk HPV-18 E6, megalin, TRAF6, Kir4.1 (basolateral K+ channel subunit), and cadherin 23; for MAGI2, include DASM1, dendrin, axin, beta- and delta-catenin, neuroligin, hyperpolarization-activated cation channels, beta1-adrenergic receptors, NMDA receptor, and TARPs; and for MAGI3 includes LPA2. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This MAGI family PDZ5 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 688547127  604 KRDSEGFGFVLRGAKaetpieEFTPTPAFpALQYLEsvdlEGVAWRAG-LRTGDFLIEVNGVSVVKVGHRQVVSLIRQGG 682
Cdd:cd06735     7 ERGPKGFGFSIRGGR------EYNNMPLY-VLRLAE----DGPAQRDGrLRVGDQILEINGESTQGMTHAQAIELIRSGG 75

                  ....*...
gi 688547127  683 S--RLVMK 688
Cdd:cd06735    76 SvvRLLLR 83