T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  432 GTVRKAGALAVKNFLVHKKNKKVESATRRKWKHYWVSLKGCTLFFYETDGRSGIDHNSVPKHAVWVENSIVQAVPEHPKK 511
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 225543222  512 DFVFCLSNSLGDAFLFQTTSQTELENWITAIHSACAAAVARHHHKED 558
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

T-lymphoma invasion and metastasis CC-Ex domain; This is the CC and Ex subdomains found in PH-CC-Ex globular domain from Tiam1 and Tiam2 proteins (T-lymphoma invasion and metastasis). The CC subdomain forms an antiparallel coiled coil with two long alpha-helices, together with the C-terminal Ex subdomain they form a small globular domain comprising three alpha-helices. The CC subdomain of the Tiam2 PHCCEx domain follows the C-terminal alpha1 helix of the PH pfam00169 subdomain through a four-residue linker.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222   572 QKIDMDEKMKKMGEMQLSSVTDSKKKKTILDQIFVWEQNLEQFQMDLFRFRCYLASLQGGELPNPKRLLAFASRPTKVAM 651
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 225543222   652 GRLGIFSVSSFHALVAAR 669
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222    842 VTQNIHIEKSDAaadNYGFLLSSVDEDGiRRLYVNSVKETGLASKKGLKAGDEILEINNR 901
Cdd:smart00228    1 EPRLVELEKGGG---GLGFSLVGGKDEG-GGVVVSSVVPGSPAAKAGLRVGDVILEVNGT 56

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  432 GTVRKAGALAVKNFLVHKKNKKVESATRRKWKHYWVSLKGCTLFFYETDGRSGIDHNSVPKHAVWVENSIVQAVPEHPKK 511
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 225543222  512 DFVFCLSNSLGDAFLFQTTSQTELENWITAIHSACAAAVARHHHKED 558
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1041 LRKVICELLETERTYVKDLNCLMERYLKPLQKE-TFLTQDELDVLFGNLTEMVEFQVEFLKTLEdgvrlvpdlEKLEKVD 1119
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKElLPLSPEEVELLFGNIEEIYEFHRIFLKSLE---------ERVEEWD 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1120 QFKkvlFSLGGSFLYYADRFKLYSAFCASHTKVPKVLVK-AKTDTAFKAFLDAQNpRQQHSSTLESYLIKPIQRVLKYPL 1198
Cdd:cd00160    72 KSG---PRIGDVFLKLAPFFKIYSEYCSNHPDALELLKKlKKFNKFFQEFLEKAE-SECGRLKLESLLLKPVQRLTKYPL 147

                         170       180       190
                  ....*....|....*....|....*....|....
gi 225543222 1199 LLRELFALTDAESEEHYHLDVAIKTMNKVASHIN 1232
Cdd:cd00160   148 LLKELLKHTPDGHEDREDLKKALEAIKEVASQVN 181

T-lymphoma invasion and metastasis CC-Ex domain; This is the CC and Ex subdomains found in PH-CC-Ex globular domain from Tiam1 and Tiam2 proteins (T-lymphoma invasion and metastasis). The CC subdomain forms an antiparallel coiled coil with two long alpha-helices, together with the C-terminal Ex subdomain they form a small globular domain comprising three alpha-helices. The CC subdomain of the Tiam2 PHCCEx domain follows the C-terminal alpha1 helix of the PH pfam00169 subdomain through a four-residue linker.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222   572 QKIDMDEKMKKMGEMQLSSVTDSKKKKTILDQIFVWEQNLEQFQMDLFRFRCYLASLQGGELPNPKRLLAFASRPTKVAM 651
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 225543222   652 GRLGIFSVSSFHALVAAR 669
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

Raf-like Ras-binding domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 225543222   766 PSWFCLPNNQPALTVVRPGDTARDTLELICKTHQLDHSAHYLRLKFLmenrvQFYIPQPEEDIYELLYKEIEIC 839
Cdd:pfam02196    1 LCRVYLPDGQRTVVQVRPGETVRDALSKLCKKRGLNPEACDVYLVGG-----DKYPLDLDTDSSTLEGEEVRVE 69

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222   452 KKVESATRRKWKHYWVSLKGCTLFFYETDGRsgiDHNSVPKHAVWVENSIVQAV--PEHPKKDFVFCLSNSL---GDAFL 526
Cdd:pfam00169    8 LKKGGGKKKSWKKRYFVLFDGSLLYYKDDKS---GKSKEPKGSISLSGCEVVEVvaSDSPKRKFCFELRTGErtgKRTYL 84

                           90       100
                   ....*....|....*....|.
gi 225543222   527 FQTTSQTELENWITAIHSACA 547
Cdd:pfam00169   85 LQAESEEERKDWIKAIQSAIR 105

PDZ domain; PDZ domains are found in diverse signaling proteins.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 225543222   859 GFLLSSVDEDGIRRLYVNSVKETGLASKKGLKAGDEILEINNR 901
Cdd:pfam00595   13 GFSLKGGSDQGDPGIFVSEVLPGGAAEAGGLKVGDRILSINGQ 55

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1033 RQLSDADKLRK-VICELLETERTYVKDLNCLMERYLKPLQKETFLTQDE----LDVLFGNLTEMVEFQVEFLKTLEDGVR 1107
Cdd:COG5422   476 ESLPKQEIKRQeAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENArrnfIKHVFANINEIYAVNSKLLKALTNRQC 555

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1108 LVPdleklekvdqfkkVLFSLGGSFLYYADRFKLYSAFCASHTKVPKVLVKAKTDTAFKAFLDAQNPRQQHSSTLE--SY 1185
Cdd:COG5422   556 LSP-------------IVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKSVNPNFARFDHEVERLDESRKLEldGY 622

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1186 LIKPIQRVLKYPLLLRELFALTDAESEEHYHLDVAIKTMNKVASHINEMQKIHEEFGAVFdqLIAEQTGEKKEVADLSMG 1265
Cdd:COG5422   623 LTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLF--HLNQQLLFKPEYVNLGLN 700

                  .
gi 225543222 1266 D 1266
Cdd:COG5422   701 D 701

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  432 GTVRKAGALAVKNFLVHKKNKKVESATRRKWKHYWVSLKGCTLFFYETDGRSGIDHNSVPKHAVWVENSIVQAVPEHPKK 511
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 225543222  512 DFVFCLSNSLGDAFLFQTTSQTELENWITAIHSACAAAVARHHHKED 558
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1041 LRKVICELLETERTYVKDLNCLMERYLKPLQKE-TFLTQDELDVLFGNLTEMVEFQVEFLKTLEdgvrlvpdlEKLEKVD 1119
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKElLPLSPEEVELLFGNIEEIYEFHRIFLKSLE---------ERVEEWD 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1120 QFKkvlFSLGGSFLYYADRFKLYSAFCASHTKVPKVLVK-AKTDTAFKAFLDAQNpRQQHSSTLESYLIKPIQRVLKYPL 1198
Cdd:cd00160    72 KSG---PRIGDVFLKLAPFFKIYSEYCSNHPDALELLKKlKKFNKFFQEFLEKAE-SECGRLKLESLLLKPVQRLTKYPL 147

                         170       180       190
                  ....*....|....*....|....*....|....
gi 225543222 1199 LLRELFALTDAESEEHYHLDVAIKTMNKVASHIN 1232
Cdd:cd00160   148 LLKELLKHTPDGHEDREDLKKALEAIKEVASQVN 181

T-lymphoma invasion and metastasis CC-Ex domain; This is the CC and Ex subdomains found in PH-CC-Ex globular domain from Tiam1 and Tiam2 proteins (T-lymphoma invasion and metastasis). The CC subdomain forms an antiparallel coiled coil with two long alpha-helices, together with the C-terminal Ex subdomain they form a small globular domain comprising three alpha-helices. The CC subdomain of the Tiam2 PHCCEx domain follows the C-terminal alpha1 helix of the PH pfam00169 subdomain through a four-residue linker.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222   572 QKIDMDEKMKKMGEMQLSSVTDSKKKKTILDQIFVWEQNLEQFQMDLFRFRCYLASLQGGELPNPKRLLAFASRPTKVAM 651
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 225543222   652 GRLGIFSVSSFHALVAAR 669
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

Raf-like Ras-binding domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 225543222   766 PSWFCLPNNQPALTVVRPGDTARDTLELICKTHQLDHSAHYLRLKFLmenrvQFYIPQPEEDIYELLYKEIEIC 839
Cdd:pfam02196    1 LCRVYLPDGQRTVVQVRPGETVRDALSKLCKKRGLNPEACDVYLVGG-----DKYPLDLDTDSSTLEGEEVRVE 69

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222   452 KKVESATRRKWKHYWVSLKGCTLFFYETDGRsgiDHNSVPKHAVWVENSIVQAV--PEHPKKDFVFCLSNSL---GDAFL 526
Cdd:pfam00169    8 LKKGGGKKKSWKKRYFVLFDGSLLYYKDDKS---GKSKEPKGSISLSGCEVVEVvaSDSPKRKFCFELRTGErtgKRTYL 84

                           90       100
                   ....*....|....*....|.
gi 225543222   527 FQTTSQTELENWITAIHSACA 547
Cdd:pfam00169   85 LQAESEEERKDWIKAIQSAIR 105

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  452 KKVESATRRKWKHYWVSLKGCTLFFYETDGrsgiDHNSVPKHAVWVENSIVQAVPEHPKKDFVFCLSNSLGDAFLFQTTS 531
Cdd:cd00821     6 LKRGGGGLKSWKKRWFVLFEGVLLYYKSKK----DSSYKPKGSIPLSGILEVEEVSPKERPHCFELVTPDGRTYYLQADS 81

                          90
                  ....*....|.
gi 225543222  532 QTELENWITAI 542
Cdd:cd00821    82 EEERQEWLKAL 92

ARHGAP21 and related proteins pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with a RhoGAP domain. These proteins functions as a GTPase-activating protein (GAP) for RHOA and CDC42. ARHGAP21 controls the Arp2/3 complex and F-actin dynamics at the Golgi complex by regulating the activity of the small GTPase Cdc42. It is recruited to the Golgi by to GTPase, ARF1, through its PH domain and its helical motif. It is also required for CTNNA1 recruitment to adherens junctions. ARHGAP21 and it related proteins all contains a PH domain and a RhoGAP domain. Some of the members have additional N-terminal domains including PDZ, SH3, and SPEC. The ARHGAP21 PH domain interacts with the GTPbound forms of both ARF1 and ARF6 ARF-binding domain/ArfBD. The members here include: ARHGAP15, ARHGAP21, and ARHGAP23. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  435 RKAGALAVKNFLVHKKNKkvesATRRKWKHYWVSLKGCTLFFYEtDGRSGIDHNSVPKHA---VWVENSIVQAVPEHPKK 511
Cdd:cd01253     1 AREGWLHYKQIVTDKGKR----VSDRSWKQAWAVLRGHSLYLYK-DKREQTPALSIELGSeqrISIRGCIVDIAYSYTKR 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 225543222  512 DFVFCLSNSLGDAFLFQTTSQTELENWITAIHS 544
Cdd:cd01253    76 KHVFRLTTSDFSEYLFQAEDRDDMLGWIKAIQE 108

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222    842 VTQNIHIEKSDAaadNYGFLLSSVDEDGiRRLYVNSVKETGLASKKGLKAGDEILEINNR 901
Cdd:smart00228    1 EPRLVELEKGGG---GLGFSLVGGKDEG-GGVVVSSVVPGSPAAKAGLRVGDVILEVNGT 56

Fungal proteins Pleckstrin homology (PH) domain, repeat 1; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents the first PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  447 VHKKNKKvesatRRKWKHYWVSLKGCTLFFY----ETDGRSGIDHNSVpkHAVwvensivqAVPEHPKKDFVFCL-SNSl 521
Cdd:cd13298    12 LLKRSRK-----TKNWKKRWVVLRPCQLSYYkdekEYKLRRVINLSEL--LAV--------APLKDKKRKNVFGIyTPS- 75

                          90       100
                  ....*....|....*....|...
gi 225543222  522 gDAFLFQTTSQTELENWITAIHS 544
Cdd:cd13298    76 -KNLHFRATSEKDANEWVEALRE 97

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1033 RQLSDADKLRK-VICELLETERTYVKDLNCLMERYLKPLQKETFLTQDE----LDVLFGNLTEMVEFQVEFLKTLEDGVR 1107
Cdd:COG5422   476 ESLPKQEIKRQeAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENArrnfIKHVFANINEIYAVNSKLLKALTNRQC 555

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1108 LVPdleklekvdqfkkVLFSLGGSFLYYADRFKLYSAFCASHTKVPKVLVKAKTDTAFKAFLDAQNPRQQHSSTLE--SY 1185
Cdd:COG5422   556 LSP-------------IVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKSVNPNFARFDHEVERLDESRKLEldGY 622

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222 1186 LIKPIQRVLKYPLLLRELFALTDAESEEHYHLDVAIKTMNKVASHINEMQKIHEEFGAVFdqLIAEQTGEKKEVADLSMG 1265
Cdd:COG5422   623 LTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLF--HLNQQLLFKPEYVNLGLN 700

                  .
gi 225543222 1266 D 1266
Cdd:COG5422   701 D 701

PDZ domains of the Na+/H+ exchange regulatory cofactor (NHERF) family (NHERF1-4), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of the Na+/H+ exchange regulatory cofactor (NHERF) family of multi-PDZ-domain-containing scaffolding proteins (NHERF1-4), and related domains. The NHERF family includes NHERF1 (also known as EBP50), NHERF2 (also known as E3KARP; TKA-1; SIP-1), NHERF3 (also known as CAP70; CLAMP; Napi-Cap-1; PDZD1) and NHERF4 (also known as IKEPP; PDZK2; Napi-Cap-2). NHERF1 and NHERF2 have tandem PDZ domains (PDZ1-2); NHERF3 and NHERF4 have four PDZ domains (PDZ1-4). NHERFs are involved in the regulation of multiple receptors or transporters, such as type II sodium-phosphate cotransporter (Npt2a), purinergic P2Y1 receptor P2Y1R, the beta2-adrenergic receptor (beta2-AR), parathyroid hormone receptor type 1 (PTHR), the lysophosphatidic acid receptors (LPARs), sodium-hydrogen exchanger 3 (NHE3), and cystic fibrosis transmembrane conductance regulator (CFTR). NHERF-PDZ1 domain interaction partners include Npt2a, purinergic P2Y1 receptor, beta2-AR, CFTR, PTHR, NH3, G-protein-coupled receptor kinase 6 (GRK6A), platelet-derived growth factor receptor (PDGFR), B1 subunit of the H+ATPase, cholesterol, receptor for activated C-kinase RACK1, aquaporin 9, among others. The NHERF PDZ2 domain interacts with fewer proteins: NHERF1 PDZ2 binds Npt2a, PTHR, beta-catenin, aquaporin 9, and RACK1; NHERF2 PDZ2 binds LPA2, P2Y1R, and NHE3, cGMP-dependent protein kinase type II (cGKII). NHERF4 PDZ1 and PDZ4 bind the epithelial Ca(2+) channels TRPV5 and TRPV6. NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. NHERF4 regulates several transporters mediating influx of xenobiotics and nutrients in the small intestine. 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 NHERF-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.

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 225543222  847 HIEKSDaaaDNYGFLLSSvdEDGIRRLYVNSVKETGLASKKGLKAGDEILEIN 899
Cdd:cd06768     4 HLVKGP---EGYGFNLHA--EKGRPGHFIREVDPGSPAERAGLKDGDRLVEVN 51

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 1; Pleckstrin is a protein found in platelets. This name is derived from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin 2 contains two PH domains and a DEP (dishvelled, egl-10, and pleckstrin) domain. Unlike pleckstrin 1, pleckstrin 2 does not contain obvious sites of PKC phosphorylation. Pleckstrin 2 plays a role in actin rearrangement, large lamellipodia and peripheral ruffle formation, and may help orchestrate cytoskeletal arrangement. The PH domains of pleckstrin 2 are thought to contribute to lamellipodia formation. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  445 FLVHKKNKkvesatRRKWKHYWVSLKGCTLFFYEtdGRSgidhNSVPKHAVWVENS-IVQAVPEHPKKDFVFCLSNSLGD 523
Cdd:cd13301     8 YLVKKGHV------VNNWKARWFVLKEDGLEYYK--KKT----DSSPKGMIPLKGCtITSPCLEYGKRPLVFKLTTAKGQ 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 225543222  524 AFLFQTTSQTELENWITAIHSACAAAVARHHHK 556
Cdd:cd13301    76 EHFFQACSREERDAWAKDITKAITCLEGGKRFA 108

Pleckstrin homology domain containing, family J member 1 Pleckstrin homology (PH) domain; PLEKHJ1 (also called GNRPX2/Guanine nucleotide-releasing protein x ). It contains a single PH domain. Very little information is known about PLEKHJ1. PLEKHJ1 has been shown to interact with IKBKG (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma) and KRT33B (keratin 33B). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  452 KKVESATRRkwkhyWVSLKGCTLFFYETDGRSgidHNSVPKHAVWVENSIVQAVPEHPKKdFVFCLSNS--LGDAFLFQT 529
Cdd:cd13258    31 KKSEVFKER-----WFKLKGNLLFYFRTNEFG---DCSEPIGAIVLENCRVQMEEITEKP-FAFSIVFNdePEKKYIFSC 101

                          90
                  ....*....|....*.
gi 225543222  530 TSQTELENWITAIHSA 545
Cdd:cd13258   102 RSEEQCEQWIEALRQA 117

Rho GTPase activating protein 2 Pleckstrin homology (PH) domain; RhoGAP2 (also called RhoGap22 or ArhGap22) are involved in cell polarity, cell morphology and cytoskeletal organization. They activate a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt, and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues resulting in regulation of cell motility. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  453 KVESATRRKWKHYWVSLKGCTLFFYETDgrsgidHNSVPKHAVWVENSIVQAV---PEHPKKDFVFCLSNSLGD------ 523
Cdd:cd13378    10 KKQRSIMKNWQQRWFVLRGDQLFYYKDE------EETKPQGCISLQGSQVNELppnPEEPGKHLFEILPGGAGDrekvpm 83

                          90       100
                  ....*....|....*....|..
gi 225543222  524 ---AFLFQTTSQTELENWITAI 542
Cdd:cd13378    84 nheAFLLMANSQSDMEDWVKAI 105

Beta-spectrin pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. The ARHGAP members here all have a PH domain upstream of their C-terminal RhoGAP domain. Some have additional N-terminal SH3 and WW domains. The members here include: ARHGAP9, ARHGAP12, ARHGAP15, and ARHGAP27. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. The PH domain of ArhGAP9 employs a non-canonical phosphoinositide binding mechanism, a variation of the spectrin- Ins(4,5)P2-binding mode, that gives rise to a unique PI binding profile, namely a preference for both PI(4,5)P2 and the PI 3-kinase products PI(3,4,5)P3 and PI(3,4)P2. This lipid binding mechanism is also employed by the PH domain of Tiam1 and Slm1. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  451 NKKVesatRRKWKHYWVSLKGCTLFFYEtDGRSGIDHN---SVPKHAVWVENSIVQAVPEHPKKDFVFCLSNSLGDAFLF 527
Cdd:cd13233    15 GKKL----RKNWSTSWVVLTSSHLLFYK-DAKSAAKSGnpySKPESSVDLRGASIEWAKEKSSRKNVFQISTVTGTEFLL 89

                          90
                  ....*....|....*...
gi 225543222  528 QTTSQTELENWITAIHSA 545
Cdd:cd13233    90 QSDNDTEIREWFDAIKAV 107

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
                  ....*....|....*....|....*..
gi 225543222  874 YVNSVKETGLASKKGLKAGDEILEINN 900
Cdd:cd06746    45 YLESVDPGGVADKAGLKKGDFLLEING 71

Ral GEF with PH domain and SH3 binding motif 1 and 2 Pleckstrin homology (PH) domain; RalGPS1 (also called Ral GEF with PH domain and SH3 binding motif 1;RALGEF2/ Ral guanine nucleotide exchange factor 2; RalA exchange factor RalGPS1; Ral guanine nucleotide exchange factor RalGPS1A2; ras-specific guanine nucleotide-releasing factor RalGPS1) and RalGPS2 (also called Ral GEF with PH domain and SH3 binding motif 2; Ral-A exchange factor RalGPS2; ras-specific guanine nucleotide-releasing factor RalGPS22). They activate small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thereby regulating various downstream cellular processes. Structurally they contain an N-terminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal PH domain. The Cdc25-like catalytic domain interacts with Ral and its PH domain ensures the correct membrane localization. Its PXXP motif is thought to interact with the SH3 domain of Grb2. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  462 WKHYWVSLKGCTLFFYETDGRSGIDHN---SVPKHAVWVENSIVqAVPEHPKKDFVFCLSNS-LGDAFLFQTTSQTELEN 537
Cdd:cd13310    23 WQRYWVQLWGTSLVYYAPKSLKGTERSdfkSEPCKIVSISGWMV-VLGDDPEHPDSFQLTDPeKGNVYKFRAGSRSNALL 101

                          90
                  ....*....|
gi 225543222  538 WITAIHSACA 547
Cdd:cd13310   102 WLKHLKDACK 111

Autophagy-related protein 26/Sterol 3-beta-glucosyltransferase Pleckstrin homology (PH) domain, repeat 1; ATG26 (also called UGT51/UDP-glycosyltransferase 51), a member of the glycosyltransferase 28 family, resulting in the biosynthesis of sterol glucoside. ATG26 in decane metabolism and autophagy. There are 32 known autophagy-related (ATG) proteins, 17 are components of the core autophagic machinery essential for all autophagy-related pathways and 15 are the additional components required only for certain pathways or species. The core autophagic machinery includes 1) the ATG9 cycling system (ATG1, ATG2, ATG9, ATG13, ATG18, and ATG27), 2) the phosphatidylinositol 3-kinase complex (ATG6/VPS30, ATG14, VPS15, and ATG34), and 3) the ubiquitin-like protein system (ATG3, ATG4, ATG5, ATG7, ATG8, ATG10, ATG12, and ATG16). Less is known about how the core machinery is adapted or modulated with additional components to accommodate the nonselective sequestration of bulk cytosol (autophagosome formation) or selective sequestration of specific cargos (Cvt vesicle, pexophagosome, or bacteria-containing autophagosome formation). The pexophagosome-specific additions include the ATG30-ATG11-ATG17 receptor-adaptors complex, the coiled-coil protein ATG25, and the sterol glucosyltransferase ATG26. ATG26 is necessary for the degradation of medium peroxisomes. It contains 2 GRAM domains and a single PH domain. PH domains are only found in eukaryotes. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 225543222  431 QGTVRKAGALavknflvHKKNKKvesatRRKWKHYWVSLKGCTLFFYETDG-----RSGIDHNSVPKhavwvensiVQAV 505
Cdd:cd13215    18 SGAVIKSGYL-------SKRSKR-----TLRYTRYWFVLKGDTLSWYNSSTdlyfpAGTIDLRYATS---------IELS 76

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 225543222  506 PEHPKKDFVFCLSNSlGDAFLFQTTSQTELENWITAI 542
Cdd:cd13215    77 KSNGEATTSFKIVTN-SRTYKFKADSETSADEWVKAL 112

PDZ domain 7 of glutamate receptor-interacting protein 1 (GRIP1) and GRIP2, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) binding proteins GRIP1 (ABP/GRIP2) and GRIP2, and related domains. GRIP1 and GRIP2 each have 7 PDZ domains. The interaction of GRIP1 and GRIP2 with GluA2/3 (AMPAR subunit) regulates AMPAR trafficking and synaptic targeting. GRIP1 has an essential role in regulating AMPAR trafficking during synaptic plasticity and learning and memory. GRIP1 and GRIP2 interact with a variety of other proteins associated with protein trafficking and internalization, for example GRIP1 also interacts with KIF5 (also known as kinesin 1), EphB receptors, scaffold protein liprin-alpha, and the rasGEF GRASP-1. 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 GRIP family PDZ7 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
                  ....*....|....*....|....*....|....*....|....*....|.
gi 225543222  852 DAAADNYGFLLSsvdeDGI--RRLYVNSVKETGLASKKGLKAGDEILEINN 900
Cdd:cd06685    11 DSDTEDFGFSVS----DGLyeKGVYVNAIRPGGPADLSGLQPYDRILQVNH 57