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 568997994  503 GVVRKAGWLFFKPLVTLQKERKLELVARRKWKQYWVTLKGCTLLFYETYGKNSTEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 568997994  583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFAKKHGKED 629
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 568997994   643 QKIDMDSKMKKMAELQLSVVSDPKNRKAIENQIRQWEQNLEKFHMDLFRMRCYLASLQGGELPNPKSLLAATSRPSKLAL 722
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 568997994   723 GRLGVLSVSSFHALVCSR 740
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains 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 568997994  911 DVQLTKtGDMTDFGFAVTVQVDEHQHlnrIFISDVLPDSLAY-GGGLRKGNEITSLNGEPVSDLDIQQMEALFSEKSVGL 989
Cdd:cd00136     1 TVTLEK-DPGGGLGFSIRGGKDGGGG---IFVSRVEPGGPAArDGRLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGEV 76

                  ....*
gi 568997994  990 TLVAR 994
Cdd:cd00136    77 TLTVR 81

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 568997994  503 GVVRKAGWLFFKPLVTLQKERKLELVARRKWKQYWVTLKGCTLLFYETYGKNSTEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 568997994  583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFAKKHGKED 629
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 568997994 1121 LRKVIQELVDTEKSYVKDLSCLFELYLEPLQNE-TFLTQDEMESLFGSLPEMLEFQKVFLETLEDAISASsdfsvletps 1199
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKElLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEW---------- 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994 1200 qfRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLE-RAKTDKAFKAFLDARNpTKQHSSTLESYLIKPVQRVLKYPL 1278
Cdd:cd00160    71 --DKSGPRIGDVFLKLAPFFKIYSEYCSNHPDALELLKkLKKFNKFFQEFLEKAE-SECGRLKLESLLLKPVQRLTKYPL 147

                         170       180       190
                  ....*....|....*....|....*....|....
gi 568997994 1279 LLKELVSLTDHESEEHYHLTEALKAMEKVASHIN 1312
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 568997994   643 QKIDMDSKMKKMAELQLSVVSDPKNRKAIENQIRQWEQNLEKFHMDLFRMRCYLASLQGGELPNPKSLLAATSRPSKLAL 722
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 568997994   723 GRLGVLSVSSFHALVCSR 740
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994    505 VRKAGWLffkplvtlqkeRKLELVARRKWKQYWVTLKGCTLLFYEtygKNSTEQNSAPRCALFAEDSIVQSVPE--HPKK 582
Cdd:smart00233    1 VIKEGWL-----------YKKSGGGKKSWKKRYFVLFNSTLLYYK---SKKDKKSYKPKGSIDLSGCTVREAPDpdSSKK 66

                            90       100       110
                    ....*....|....*....|....*....|....*.
gi 568997994    583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACA 618
Cdd:smart00233   67 PHCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 102

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains 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 568997994  911 DVQLTKtGDMTDFGFAVTVQVDEHQHlnrIFISDVLPDSLAY-GGGLRKGNEITSLNGEPVSDLDIQQMEALFSEKSVGL 989
Cdd:cd00136     1 TVTLEK-DPGGGLGFSIRGGKDGGGG---IFVSRVEPGGPAArDGRLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGEV 76

                  ....*
gi 568997994  990 TLVAR 994
Cdd:cd00136    77 TLTVR 81

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 568997994   924 GFAVTVQVDEHQHLNRIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSD---LDIQQM 978
Cdd:pfam00595   11 GLGFSLKGGSDQGDPGIFVSEVLPGGAAEAGGLKVGDRILSINGQDVENmthEEAVLA 68

Periplasmic serine protease, S1-C subfamily, contain C-terminal PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568997994  940 IFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDiqQMEALFSEKSVGLTLvarPVTTRR 1000
Cdd:COG0265   203 VLVARVEPGSPAAKAGLRPGDVILAVDGKPVTSAR--DLQRLLASLKPGDTV---TLTVLR 258

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 568997994  503 GVVRKAGWLFFKPLVTLQKERKLELVARRKWKQYWVTLKGCTLLFYETYGKNSTEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNKKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 568997994  583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFAKKHGKED 629
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 568997994 1121 LRKVIQELVDTEKSYVKDLSCLFELYLEPLQNE-TFLTQDEMESLFGSLPEMLEFQKVFLETLEDAISASsdfsvletps 1199
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKElLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEW---------- 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994 1200 qfRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLE-RAKTDKAFKAFLDARNpTKQHSSTLESYLIKPVQRVLKYPL 1278
Cdd:cd00160    71 --DKSGPRIGDVFLKLAPFFKIYSEYCSNHPDALELLKkLKKFNKFFQEFLEKAE-SECGRLKLESLLLKPVQRLTKYPL 147

                         170       180       190
                  ....*....|....*....|....*....|....
gi 568997994 1279 LLKELVSLTDHESEEHYHLTEALKAMEKVASHIN 1312
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 568997994   643 QKIDMDSKMKKMAELQLSVVSDPKNRKAIENQIRQWEQNLEKFHMDLFRMRCYLASLQGGELPNPKSLLAATSRPSKLAL 722
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 568997994   723 GRLGVLSVSSFHALVCSR 740
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994    505 VRKAGWLffkplvtlqkeRKLELVARRKWKQYWVTLKGCTLLFYEtygKNSTEQNSAPRCALFAEDSIVQSVPE--HPKK 582
Cdd:smart00233    1 VIKEGWL-----------YKKSGGGKKSWKKRYFVLFNSTLLYYK---SKKDKKSYKPKGSIDLSGCTVREAPDpdSSKK 66

                            90       100       110
                    ....*....|....*....|....*....|....*.
gi 568997994    583 EHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACA 618
Cdd:smart00233   67 PHCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 102

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994   505 VRKAGWLFfkplvtlqkerKLELVARRKWKQYWVTLKGCTLLFYEtygKNSTEQNSAPRCALFAEDSIVQSV--PEHPKK 582
Cdd:pfam00169    1 VVKEGWLL-----------KKGGGKKKSWKKRYFVLFDGSLLYYK---DDKSGKSKEPKGSISLSGCEVVEVvaSDSPKR 66

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 568997994   583 EHVFCL---SNSCGDVYLFQATSQTDLENWVTAIHSACA 618
Cdd:pfam00169   67 KFCFELrtgERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

Exchange Factor for ARF6 Pleckstrin homology (PH) domain; EFA6 (also called PSD/pleckstrin and Sec7 domain containing) is an guanine nucleotide exchange factor for ADP ribosylation factor 6 (ARF6), which is involved in membrane recycling. EFA6 has four structurally related polypeptides: EFA6A, EFA6B, EFA6C and EFA6D. It consists of a N-terminal proline rich region (PR), a SEC7 domain, a PH domain, a PR, a coiled-coil region, and a C-terminal PR. The EFA6 PH domain regulates its association with the plasma membrane. EFA6 activates Arf6 through its Sec7 catalytic domain and modulates this activity through its C-terminal domain, which rearranges the actin cytoskeleton in fibroblastic cell lines. 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 568997994  501 EQGVVRKAGWLFFKplVTLQKERKLELVARRKWKQYWVTLKGCTLLFY-ETYGKNSTEQNSAPRCALFAEDSIVQSVPEH 579
Cdd:cd13295     2 PNAVEYKKGYLMRK--CCADPDGKKTPFGKRGWKMFYATLKGLVLYLHkDEYGCKKALRYESLRNAISVHHSLATKATDY 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 568997994  580 PKKEHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSACASLFA 622
Cdd:cd13295    80 TKKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSA 122

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 568997994  505 VRKAGWLffkplvtLQKERKlelvaRRKWKQYWVTLKGCTLLFYetygKNSTE---QNSAPRCALFAedsiVQSVPEHpK 581
Cdd:cd13298     6 VLKSGYL-------LKRSRK-----TKNWKKRWVVLRPCQLSYY----KDEKEyklRRVINLSELLA----VAPLKDK-K 64

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 568997994  582 KEHVFCL-SNScgDVYLFQATSQTDLENWVTAIHS 615
Cdd:cd13298    65 RKNVFGIyTPS--KNLHFRATSEKDANEWVEALRE 97

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains 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 568997994  911 DVQLTKtGDMTDFGFAVTVQVDEHQHlnrIFISDVLPDSLAY-GGGLRKGNEITSLNGEPVSDLDIQQMEALFSEKSVGL 989
Cdd:cd00136     1 TVTLEK-DPGGGLGFSIRGGKDGGGG---IFVSRVEPGGPAArDGRLRVGDRILEVNGVSLEGLTHEEAVELLKSAGGEV 76

                  ....*
gi 568997994  990 TLVAR 994
Cdd:cd00136    77 TLTVR 81

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 568997994   924 GFAVTVQVDEHQHLNRIFISDVLPDSLAYGGGLRKGNEITSLNGEPVSD---LDIQQM 978
Cdd:pfam00595   11 GLGFSLKGGSDQGDPGIFVSEVLPGGAAEAGGLKVGDRILSINGQDVENmthEEAVLA 68

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 568997994  503 GVVRKAGWLffkplvtlQKERKLelvaRRKWKQYWVTLKGCTLLFYETygknstEQNSAPRCALFAEDSIVQSVPEHPKK 582
Cdd:cd13378     1 EGVLKAGWL--------KKQRSI----MKNWQQRWFVLRGDQLFYYKD------EEETKPQGCISLQGSQVNELPPNPEE 62

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 568997994  583 --EHVFCLS-NSCGD---------VYLFQATSQTDLENWVTAI 613
Cdd:cd13378    63 pgKHLFEILpGGAGDrekvpmnheAFLLMANSQSDMEDWVKAI 105

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994  530 RRKWKQYWVTLKGCTLLFYEtygknSTEQNSAPRCALFAEDSIVQSVPEHPKKEHVFCLSNSCGDVYLFQATSQTDLENW 609
Cdd:cd13301    16 VNNWKARWFVLKEDGLEYYK-----KKTDSSPKGMIPLKGCTITSPCLEYGKRPLVFKLTTAKGQEHFFQACSREERDAW 90

                          90
                  ....*....|....*.
gi 568997994  610 VTAIHSACASLFAKKH 625
Cdd:cd13301    91 AKDITKAITCLEGGKR 106

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994 1108 PRPLARHLSDADRLRK-VIQELVDTEKSYVKDLSCLFELYLEPLQNETFLTQDEMEslfgslpemlEFQKVFLETLEDAI 1186
Cdd:COG5422   471 PKEVWESLPKQEIKRQeAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENARR----------NFIKHVFANINEIY 540

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994 1187 SASSDFSVLETPSQ-FRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLERAK-TDKAFKAFLD----ARNPTKQHss 1260
Cdd:COG5422   541 AVNSKLLKALTNRQcLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKsVNPNFARFDHeverLDESRKLE-- 618

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 568997994 1261 tLESYLIKPVQRVLKYPLLLKELVSLTDHESEEHYHLTEALKAMEKVASHINEMQKIYEDYGMVF 1325
Cdd:COG5422   619 -LDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLF 682

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568997994  530 RRKWKQYWVTLKGCTLLFYETygKNSTEQNSAPRCAlfAEDSI------VQSVPEHPKKEHVFCLSNSCGDVYLFQATSQ 603
Cdd:cd13233    19 RKNWSTSWVVLTSSHLLFYKD--AKSAAKSGNPYSK--PESSVdlrgasIEWAKEKSSRKNVFQISTVTGTEFLLQSDND 94

                          90
                  ....*....|...
gi 568997994  604 TDLENWVTAIHSA 616
Cdd:cd13233    95 TEIREWFDAIKAV 107

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and, with the exception of CNK3, a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from mammals, chickens, amphibians, fish, and crustacea. 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 568997994  500 KEQGVVRKAGWLFFKplvtlqKERKLELvaRRKWKQYWVTLKGCTLLFYetygkNSTEQNSAPRCALFAEDSIVQSvpEH 579
Cdd:cd01260     8 KDLGRGDCQGWLWKK------KEAKSFF--GQKWKKYWFVLKGSSLYWY-----SNQQDEKAEGFINLPDFKIERA--SE 72

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 568997994  580 PKKEHVFCLSNSCGDVYLFQATSQTDLENWVTAIHSA 616
Cdd:cd01260    73 CKKKYAFKACHPKIKTFYFAAENLDDMNKWLSKLNMA 109

circularly permuted first PDZ domain (PDZ1) of Escherichia coli periplasmic serine endoprotease DegP and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of Escherichia coli DegP (also known as heat shock protein DegP and Protease Do) and related domains. DegP belongs to the HtrA family of housekeeping proteases. It acts as a protease, degrading transiently denatured and unfolded or misfolded proteins which accumulate in the periplasm following heat shock or other stress conditions, and as a molecular chaperone at low temperatures. DegP has two PDZ domains in addition to the protease domain; its PDZ1 domain is responsible for identifying the distinct substrate sequences that affect degradation (degron) of the substrate sequence, and its PDZ2 domain is responsible for combining with other DegP monomers to form a stable oligomer structure. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This DegP family PDZ domain 1 is a circularly permuted PDZ domain which places beta-strand A on the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                          10        20        30
                  ....*....|....*....|....*....|....
gi 568997994  940 IFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDL 973
Cdd:cd10839    27 ALVAQVLPDSPAAKAGLKAGDVILSLNGKPITSS 60

PDZ domain 2 of harmonin isoforms a, b, and c, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of harmonin isoforms a, b, and c, and related domains. Harmonin (also known as Usher Type 1C, PDZ-73 and AIE-75) is a key organizer of the Usher (USH) protein interactome. USH syndrome is the leading cause of hereditary sensory deaf-blindness in humans; three clinically distinct types of USH have been identified, type 1 to 3. The gene encoding harmonin (USH1C) is the causative gene for the USH type 1C phenotype. There are at least 10 alternatively spliced isoforms of harmonin, which are divided into three subclasses (a, b, and c). All isoforms contain the first two PDZ domains and the first coiled-coil domain. The a and b isoforms all have a third PDZ domain. The different PDZ domains are responsible for interactions with all known Usher syndrome type 1 proteins, and most Usher syndrome type 2 proteins. 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 harmonin 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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 568997994  940 IFISDVLPDSLAYGGGLRKGNEITSLNGEPVSDLDIQQ-MEALFSEKSvgLTLVAR 994
Cdd:cd06738    29 IFISNVKPGSLAEEVGLEVGDQIVEVNGTSFTNVDHKEaVMALKSSRH--LTITVR 82