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 442630403  851 GAVRKAGFLSVKKWLLRKKH-QIELARKRGWKGYWVCLKGTTLLFYPCDSREGRSVEAAPKHLIIVDGAIMQPIPEHPKR 929
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNkKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 442630403  930 DYIFCLSTAFGDAYLFQAPCQVELENWVNSIHSACAAAFARHRGKTG 976
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

WASP homology region 1; Region of the Wiskott-Aldrich syndrome protein (WASp) that contains point mutations in the majority of patients with WAS. Unknown function. Ena-like WH1 domains bind polyproline-containing peptides, and that Homer contains a WH1 domain.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403     35 LSSFRLWAEVFHVSASGAGTVKWQQVSEDLvPVNITCIQDSPECIFHITAYNSQvDKILDVRLVQPGTRIGQASECFVYW 114
Cdd:smart00461    1 LGSQCIILARAVVQLYDADTKKWVPTGEGG-AANLVIDKNQRSYFFRIVGIKGQ-DKVIWNQELYKNFKYNQATPTFHQW 78

                            90       100
                    ....*....|....*....|....*.
gi 442630403    115 KdpMTNDTWGLNFTSPIDAKQFRECC 140
Cdd:smart00461   79 A--DDKCVYGLNFASEEEAKKFRKKV 102

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 442630403   990 KAIESDHKLKHMAELQQSVVTDQETRHQIQTQILQWEENLERLHCEQFRLRCYMASLQSGELPNPKSLLTHVSRPTKNTL 1069
Cdd:pfam18385    1 QKIDMDEKMKKMGEMQLSSVTDAKKKKTILDQVFLWGENTEQERLSLFLFAQYLAECQGAELPCPTYMLIYASETDKLAS 80

                           90
                   ....*....|....*...
gi 442630403  1070 NKLGVFTVSSFHAFICAR 1087
Cdd:pfam18385   81 GTLGVARVGTYQSQVAAR 98

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 442630403  851 GAVRKAGFLSVKKWLLRKKH-QIELARKRGWKGYWVCLKGTTLLFYPCDSREGRSVEAAPKHLIIVDGAIMQPIPEHPKR 929
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNkKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 442630403  930 DYIFCLSTAFGDAYLFQAPCQVELENWVNSIHSACAAAFARHRGKTG 976
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; 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. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403   1459 VVMELVDTERTYVKHLNNLLEHYLEPM-KRETFLSNAEINALFGNIHEIVTFQRQFLQNLEESLDLEPDFNKFehcgqfr 1537
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLkKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDSVER------- 73

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403   1538 nvlfaIGSAFLYYVNHFKLYSSFCASHSKAQKVLHPNEGNHALQEFLAARNPKQQHSS-TLESYLIKPIQRILKYPLLLQ 1616
Cdd:smart00325   74 -----IGDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCRRlTLESLLLKPVQRLTKYPLLLK 148

                           170       180       190
                    ....*....|....*....|....*....|..
gi 442630403   1617 QMRNLTDTRADEHVHLCEALKGMEKVAEHINE 1648
Cdd:smart00325  149 ELLKHTPEDHEDREDLKKALKAIKELANQVNE 180

WASP homology region 1; Region of the Wiskott-Aldrich syndrome protein (WASp) that contains point mutations in the majority of patients with WAS. Unknown function. Ena-like WH1 domains bind polyproline-containing peptides, and that Homer contains a WH1 domain.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403     35 LSSFRLWAEVFHVSASGAGTVKWQQVSEDLvPVNITCIQDSPECIFHITAYNSQvDKILDVRLVQPGTRIGQASECFVYW 114
Cdd:smart00461    1 LGSQCIILARAVVQLYDADTKKWVPTGEGG-AANLVIDKNQRSYFFRIVGIKGQ-DKVIWNQELYKNFKYNQATPTFHQW 78

                            90       100
                    ....*....|....*....|....*.
gi 442630403    115 KdpMTNDTWGLNFTSPIDAKQFRECC 140
Cdd:smart00461   79 A--DDKCVYGLNFASEEEAKKFRKKV 102

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 442630403    853 VRKAGFLSVKKWllrkkhqielARKRGWKGYWVCLKGTTLLFYPCDSREGRSveaAPKHLIIVDGAIMQPIPE--HPKRD 930
Cdd:smart00233    1 VIKEGWLYKKSG----------GGKKSWKKRYFVLFNSTLLYYKSKKDKKSY---KPKGSIDLSGCTVREAPDpdSSKKP 67

                            90       100       110
                    ....*....|....*....|....*....|....*
gi 442630403    931 YIFCLSTAFGDAYLFQAPCQVELENWVNSIHSACA 965
Cdd:smart00233   68 HCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 102

Raf-like Ras-binding domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 442630403  1132 TFKVAMPDNAYSTVYLRDAMSVEEFLASACARRNLNPMEHFVRVKKRrdmedHNYFVPHRNDLIenYLHNHEfVEVC 1208
Cdd:pfam02196    1 LCRVYLPDGQRTVVQVRPGETVRDALSKLCKKRGLNPEACDVYLVGG-----DKYPLDLDTDSS--TLEGEE-VRVE 69

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        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403   1211 ILYQVELQRTTLEqmWGFSVEAElienaeRQDELCCYVSRVEDKSVAMHNGIIKGDEIMVINGAIVSDLDMMYLESVLQE 1290
Cdd:smart00228    1 EPRLVELEKGGGG--LGFSLVGG------KDEGGGVVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKK 72

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 442630403 1215 VELQRTTLEQmWGFSVEAElienaeRQDELCCYVSRVEDKSVAMHNGIIK-GDEIMVINGAIVSDLDMMYLESVLQE-EQ 1292
Cdd:cd00136     2 VTLEKDPGGG-LGFSIRGG------KDGGGGIFVSRVEPGGPAARDGRLRvGDRILEVNGVSLEGLTHEEAVELLKSaGG 74

                  ....*..
gi 442630403 1293 SLSMMMR 1299
Cdd:cd00136    75 EVTLTVR 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 442630403  851 GAVRKAGFLSVKKWLLRKKH-QIELARKRGWKGYWVCLKGTTLLFYPCDSREGRSVEAAPKHLIIVDGAIMQPIPEHPKR 929
Cdd:cd01230     1 GAVRKAGWLSVKNFLVHKKNkKVELATRRKWKKYWVCLKGCTLLFYECDERSGIDENSEPKHALFVEGSIVQAVPEHPKK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 442630403  930 DYIFCLSTAFGDAYLFQAPCQVELENWVNSIHSACAAAFARHRGKTG 976
Cdd:cd01230    81 DFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACASAFARQHGKED 127

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; 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. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403   1459 VVMELVDTERTYVKHLNNLLEHYLEPM-KRETFLSNAEINALFGNIHEIVTFQRQFLQNLEESLDLEPDFNKFehcgqfr 1537
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLkKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDSVER------- 73

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403   1538 nvlfaIGSAFLYYVNHFKLYSSFCASHSKAQKVLHPNEGNHALQEFLAARNPKQQHSS-TLESYLIKPIQRILKYPLLLQ 1616
Cdd:smart00325   74 -----IGDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCRRlTLESLLLKPVQRLTKYPLLLK 148

                           170       180       190
                    ....*....|....*....|....*....|..
gi 442630403   1617 QMRNLTDTRADEHVHLCEALKGMEKVAEHINE 1648
Cdd:smart00325  149 ELLKHTPEDHEDREDLKKALKAIKELANQVNE 180

WASP homology region 1; Region of the Wiskott-Aldrich syndrome protein (WASp) that contains point mutations in the majority of patients with WAS. Unknown function. Ena-like WH1 domains bind polyproline-containing peptides, and that Homer contains a WH1 domain.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442630403     35 LSSFRLWAEVFHVSASGAGTVKWQQVSEDLvPVNITCIQDSPECIFHITAYNSQvDKILDVRLVQPGTRIGQASECFVYW 114
Cdd:smart00461    1 LGSQCIILARAVVQLYDADTKKWVPTGEGG-AANLVIDKNQRSYFFRIVGIKGQ-DKVIWNQELYKNFKYNQATPTFHQW 78

                            90       100
                    ....*....|....*....|....*.
gi 442630403    115 KdpMTNDTWGLNFTSPIDAKQFRECC 140
Cdd:smart00461   79 A--DDKCVYGLNFASEEEAKKFRKKV 102

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 442630403    853 VRKAGFLSVKKWllrkkhqielARKRGWKGYWVCLKGTTLLFYPCDSREGRSveaAPKHLIIVDGAIMQPIPE--HPKRD 930
Cdd:smart00233    1 VIKEGWLYKKSG----------GGKKSWKKRYFVLFNSTLLYYKSKKDKKSY---KPKGSIDLSGCTVREAPDpdSSKKP 67

                            90       100       110
                    ....*....|....*....|....*....|....*
gi 442630403    931 YIFCLSTAFGDAYLFQAPCQVELENWVNSIHSACA 965
Cdd:smart00233   68 HCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 102

Raf-like Ras-binding domain;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 442630403  1132 TFKVAMPDNAYSTVYLRDAMSVEEFLASACARRNLNPMEHFVRVKKRrdmedHNYFVPHRNDLIenYLHNHEfVEVC 1208
Cdd:pfam02196    1 LCRVYLPDGQRTVVQVRPGETVRDALSKLCKKRGLNPEACDVYLVGG-----DKYPLDLDTDSS--TLEGEE-VRVE 69

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 442630403  862 KKWLLRKKHQIELAR-----KRGWKGYWVCLKGTTLLF----YPCdsrEGRSVEAAPKHLIIVDGAIMQPIPEHPKRDYI 932
Cdd:cd13295     9 KGYLMRKCCADPDGKktpfgKRGWKMFYATLKGLVLYLhkdeYGC---KKALRYESLRNAISVHHSLATKATDYTKKPHV 85

                          90       100       110
                  ....*....|....*....|....*....|....
gi 442630403  933 FCLSTAFGDAYLFQAPCQVELENWVNSIHSACAA 966
Cdd:cd13295    86 FRLRTADWREYLFQASDTKEMQSWIEAINLVAAA 119

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 442630403  855 KAGFLsVKKWLLRKKhqielarkrgWKGYWVCLKGTTLLFYpcdsrEGRSvEAAPKHLIIVDGA-IMQPIPEHPKRDYIF 933
Cdd:cd13301     5 KEGYL-VKKGHVVNN----------WKARWFVLKEDGLEYY-----KKKT-DSSPKGMIPLKGCtITSPCLEYGKRPLVF 67

                          90       100       110
                  ....*....|....*....|....*....|
gi 442630403  934 CLSTAFGDAYLFQAPCQVELENWVNSIHSA 963
Cdd:cd13301    68 KLTTAKGQEHFFQACSREERDAWAKDITKA 97

Beta-spectrin pleckstrin homology (PH) domain; Beta spectrin binds actin and functions as a major component of the cytoskeleton underlying cellular membranes. Beta spectrin consists of multiple spectrin repeats followed by a PH domain, which binds to inositol-1,4,5-trisphosphate. The PH domain of beta-spectrin is thought to play a role in the association of spectrin with the plasma membrane of cells. 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 442630403  865 LLRKkHQIELARKRG----WKGYWVCLKGTTLLFYPcDSREGRSVE----AAPkhlIIVDGAIMQPIPEHPKRDYIFCLS 936
Cdd:cd10571     5 LERK-HEWESGGKKAsnrsWKNVYTVLRGQELSFYK-DQKAAKSGItyaaEPP---LNLYNAVCEVASDYTKKKHVFRLK 79

                          90       100
                  ....*....|....*....|....*..
gi 442630403  937 TAFGDAYLFQAPCQVELENWVNSIHSA 963
Cdd:cd10571    80 LSDGAEFLFQAKDEEEMNQWVKKISFA 106

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 442630403  855 KAGFLSVKKWLLRKKHQielarKRGWKGYWVCLKGTTLLFYpcdsREGRSVEAAPKH----LIIVD--GAIMQPIPEHPK 928
Cdd:cd13233     2 KQGLLNKTKIAENGKKL-----RKNWSTSWVVLTSSHLLFY----KDAKSAAKSGNPyskpESSVDlrGASIEWAKEKSS 72

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 442630403  929 RDYIFCLSTAFGDAYLFQAPCQVELENWVNSIHSA 963
Cdd:cd13233    73 RKNVFQISTVTGTEFLLQSDNDTEIREWFDAIKAV 107

Myosin X Pleckstrin homology (PH) domain, repeat 2; MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C-terminus. The first PH domain in the MyoX tail is a split-PH domain, interupted by the second PH domain such that PH 1a and PH 1b flanks PH 2. The third PH domain (PH 3) follows the PH 1b domain. This cd contains the second 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 442630403  864 WLLRKKHQIELARKRGWKGYWVCLKGTTLLFYPCDSrEGrsveAAPKHLIIVdGAIMQPIPEHPKrDYIFCLSTAfGDAY 943
Cdd:cd13296     4 WLTKKGGGSSTLSRRNWKSRWFVLRDTVLKYYENDQ-EG----EKLLGTIDI-RSAKEIVDNDPK-ENRLSITTE-ERTY 75

                          90       100
                  ....*....|....*....|....
gi 442630403  944 LFQAPCQVELENWVNSIHSACAAA 967
Cdd:cd13296    76 HLVAESPEDASQWVNVLTRVISAT 99

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 442630403 1215 VELQRTTLEQmWGFSVEAElienaeRQDELCCYVSRVEDKSVAMHNGIIK-GDEIMVINGAIVSDLDMMYLESVLQE-EQ 1292
Cdd:cd00136     2 VTLEKDPGGG-LGFSIRGG------KDGGGGIFVSRVEPGGPAARDGRLRvGDRILEVNGVSLEGLTHEEAVELLKSaGG 74

                  ....*..
gi 442630403 1293 SLSMMMR 1299
Cdd:cd00136    75 EVTLTVR 81

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single 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 442630403  847 FNCTGAVRKAGFLSvKKWLLRKKHQielarKRgwkgyWVCLKGtTLLFYpCDSREGRSveaaPKHLIIVDGAIMQPIPEH 926
Cdd:cd13288     2 ATCNSPVDKEGYLW-KKGERNTSYQ-----KR-----WFVLKG-NLLFY-FEKKGDRE----PLGVIVLEGCTVELAEDA 64

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 442630403  927 PKrdYIFCLSTAFGDA--YLFQAPCQVELENWVNSIhsACA 965
Cdd:cd13288    65 EP--YAFAIRFDGPGArsYVLAAENQEDMESWMKAL--SRA 101

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 442630403 1215 VELQRTTlEQMWGFSVEAELIENAERQD-ELCCYVSRVEDKSVAMHNGIIKGDEIMVINGAIVSDLD 1280
Cdd:cd06713     6 IILEKQD-NETFGFEIQTYGLHHKNSNEvEMCTYVCRVHEDSPAYLAGLTAGDVILSVNGVSVEGAS 71

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 442630403  853 VRKAGflsvkkWLLRKKHqielaRKRGWKGYWVCLKGTTLLFYPcDSREGRsveaaPKHLI-IVDGAIMQPIPEHpKRDY 931
Cdd:cd13298     6 VLKSG------YLLKRSR-----KTKNWKKRWVVLRPCQLSYYK-DEKEYK-----LRRVInLSELLAVAPLKDK-KRKN 67

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 442630403  932 IFCLSTAfGDAYLFQAPCQVELENWVNSIHsacaaAFARHR 972
Cdd:cd13298    68 VFGIYTP-SKNLHFRATSEKDANEWVEALR-----EEFRLD 102

PDZ domain of partitioning defective 6 (Par6), Drosophila Rho GTPase-activating protein 100F (RhoGAP100F), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Par6 (also known as PAR6 or Par-6), RhoGAP100F, and related domains. Par6 is part of a conserved machinery that directs metazoan cell polarity, a process necessary for the function of diverse cell types. Par6 forms a cell polarity-regulatory complex with atypical protein kinase C (aPKC) and Par3. Par6 can also directly associate with PALS1 (proteins associated with Lin7, also known as Stardust) providing a link between the Par3/aPKC/Par6 complex and the PALS1-PATJ (protein-associated TJ) complex. Binding partners of the Par6-PDZ domain include Par3, PALS1/Stardust; leucine-rich repeat-containing protein netrin-G ligand-2 (NGL-2), human crumbs (CRB3) involve in the morphogenesis of the tight junctions in mammalian epithelial cells, and PAR-6 co-operates with the Par6 semi-CRIB domain to bind CDC42. CDC42 regulates the Par6 PDZ domain through an allosteric CRIB-PDZ transition. Drosophila RhoGAP100F, also known as synapse defective protein 1 homolog (syd-1 homolog), is a GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound form. The RhoGAP100F-PDZ domain binds the neurexin C terminus to control synapse formation at the Drosophila neuromuscular junction. 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 Par6-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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 442630403 1247 YVSRVEDKSVAMHNGIIK-GDEIMVINGAIVSDLDMmylesvlqeEQSLSMMMRSSR 1302
Cdd:cd06718    30 FISRLVLGSLADSTGLLAvGDEILEVNGVEVTGKSL---------DDVTDMMVAPTR 77