T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, C-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. The DH domain of Tiam1 interacts with Switch regions 1 and 2 of Rac1 which blocks magnesium binding and GDP is released. 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. 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 557948067 219 QKIYEDYGMVFDQLVAEQSGTEKEVTELSMGELLMHSTVSWLNPFLSLGKARKDIELTVFVFKRAVILVYKENCKLKKKL 298
Cdd:cd01255    1 QKIHEEYGAVFDQLIREQSGTKKEVADLSMGDLLLYGTVEWLNPPSSLGKVKKEPELAVFVFKTAVVLVCKERSKQKKKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067 299 PSNSRPAHnSADLDPFKFRWLIPISALQVRLGNTAGTENNSTWELIHTKSEIEGRPETIFQLCCSDSENKTSIVKVIRSI 378
Cdd:cd01255   81 MGSHRKSS-YEERDPFRFRHLIPVSALQVRNSNTADTESRCLWELIHTKSELEGRPEKVFQLCCSTPEFKNAFLKVIRSI 159

                        170
                 ....*....|...
gi 557948067 379 LRENFRRHIKCEL 391
Cdd:cd01255  160 LREKVRRQSSKTE 172

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, C-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. The DH domain of Tiam1 interacts with Switch regions 1 and 2 of Rac1 which blocks magnesium binding and GDP is released. 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. 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 557948067 219 QKIYEDYGMVFDQLVAEQSGTEKEVTELSMGELLMHSTVSWLNPFLSLGKARKDIELTVFVFKRAVILVYKENCKLKKKL 298
Cdd:cd01255    1 QKIHEEYGAVFDQLIREQSGTKKEVADLSMGDLLLYGTVEWLNPPSSLGKVKKEPELAVFVFKTAVVLVCKERSKQKKKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067 299 PSNSRPAHnSADLDPFKFRWLIPISALQVRLGNTAGTENNSTWELIHTKSEIEGRPETIFQLCCSDSENKTSIVKVIRSI 378
Cdd:cd01255   81 MGSHRKSS-YEERDPFRFRHLIPVSALQVRNSNTADTESRCLWELIHTKSELEGRPEKVFQLCCSTPEFKNAFLKVIRSI 159

                        170
                 ....*....|...
gi 557948067 379 LRENFRRHIKCEL 391
Cdd:cd01255  160 LREKVRRQSSKTE 172

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 557948067  25 LRKVIQELVDTEKSYVKDLSCLFELYLEPLQNE-TFLTQDEMESLFGSLPEMLEFQKVFLETLEDAISASsdfsvletps 103
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKElLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEW---------- 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067 104 qfRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLE-RAKTDKAFKAFLDARNpTKQHSSTLESYLIKPVQRVLKYPL 182
Cdd:cd00160   71 --DKSGPRIGDVFLKLAPFFKIYSEYCSNHPDALELLKkLKKFNKFFQEFLEKAE-SECGRLKLESLLLKPVQRLTKYPL 147

                        170       180       190
                 ....*....|....*....|....*....|....
gi 557948067 183 LLKELVSLTDHESEEHYHLTEALKAMEKVASHIN 216
Cdd:cd00160  148 LLKELLKHTPDGHEDREDLKKALEAIKEVASQVN 181

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067   12 PRPLARHLSDADRLRK-VIQELVDTEKSYVKDLSCLFELYLEPLQNETFLTQDEMEslfgslpemlEFQKVFLETLEDAI 90
Cdd:COG5422   471 PKEVWESLPKQEIKRQeAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENARR----------NFIKHVFANINEIY 540

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067   91 SASSDFSVLETPSQ-FRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLERAK-TDKAFKAFLD----ARNPTKQHss 164
Cdd:COG5422   541 AVNSKLLKALTNRQcLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKsVNPNFARFDHeverLDESRKLE-- 618

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 557948067  165 tLESYLIKPVQRVLKYPLLLKELVSLTDHESEEHYHLTEALKAMEKVASHINEMQKIYEDYGMVF 229
Cdd:COG5422   619 -LDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLF 682

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, C-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. The DH domain of Tiam1 interacts with Switch regions 1 and 2 of Rac1 which blocks magnesium binding and GDP is released. 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. 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 557948067 219 QKIYEDYGMVFDQLVAEQSGTEKEVTELSMGELLMHSTVSWLNPFLSLGKARKDIELTVFVFKRAVILVYKENCKLKKKL 298
Cdd:cd01255    1 QKIHEEYGAVFDQLIREQSGTKKEVADLSMGDLLLYGTVEWLNPPSSLGKVKKEPELAVFVFKTAVVLVCKERSKQKKKL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067 299 PSNSRPAHnSADLDPFKFRWLIPISALQVRLGNTAGTENNSTWELIHTKSEIEGRPETIFQLCCSDSENKTSIVKVIRSI 378
Cdd:cd01255   81 MGSHRKSS-YEERDPFRFRHLIPVSALQVRNSNTADTESRCLWELIHTKSELEGRPEKVFQLCCSTPEFKNAFLKVIRSI 159

                        170
                 ....*....|...
gi 557948067 379 LRENFRRHIKCEL 391
Cdd:cd01255  160 LREKVRRQSSKTE 172

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 557948067  25 LRKVIQELVDTEKSYVKDLSCLFELYLEPLQNE-TFLTQDEMESLFGSLPEMLEFQKVFLETLEDAISASsdfsvletps 103
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKElLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEW---------- 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067 104 qfRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLE-RAKTDKAFKAFLDARNpTKQHSSTLESYLIKPVQRVLKYPL 182
Cdd:cd00160   71 --DKSGPRIGDVFLKLAPFFKIYSEYCSNHPDALELLKkLKKFNKFFQEFLEKAE-SECGRLKLESLLLKPVQRLTKYPL 147

                        170       180       190
                 ....*....|....*....|....*....|....
gi 557948067 183 LLKELVSLTDHESEEHYHLTEALKAMEKVASHIN 216
Cdd:cd00160  148 LLKELLKHTPDGHEDREDLKKALEAIKEVASQVN 181

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067   12 PRPLARHLSDADRLRK-VIQELVDTEKSYVKDLSCLFELYLEPLQNETFLTQDEMEslfgslpemlEFQKVFLETLEDAI 90
Cdd:COG5422   471 PKEVWESLPKQEIKRQeAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENARR----------NFIKHVFANINEIY 540

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 557948067   91 SASSDFSVLETPSQ-FRKLLFSLGGSFLYYADHFKLYSGFCANHIKVQRVLERAK-TDKAFKAFLD----ARNPTKQHss 164
Cdd:COG5422   541 AVNSKLLKALTNRQcLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKsVNPNFARFDHeverLDESRKLE-- 618

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 557948067  165 tLESYLIKPVQRVLKYPLLLKELVSLTDHESEEHYHLTEALKAMEKVASHINEMQKIYEDYGMVF 229
Cdd:COG5422   619 -LDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAENRGDLF 682