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 1958762347  724 DPTMPTYKQGILARKMHHDADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGQwlDGESLVGHMMDEPVGVHHSLASPATH 803
Cdd:cd13295      1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYG--CKKALRYESLRNAISVHHSLATKATD 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1958762347  804 YTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAATHSAPPFP 851
Cdd:cd13295     79 YTKKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSAPPLP 126

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 1958762347  724 DPTMPTYKQGILARKMHHDADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGQwlDGESLVGHMMDEPVGVHHSLASPATH 803
Cdd:cd13295      1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYG--CKKALRYESLRNAISVHHSLATKATD 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1958762347  804 YTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAATHSAPPFP 851
Cdd:cd13295     79 YTKKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSAPPLP 126

Sec7 domain; Domain named after the S. cerevisiae SEC7 gene product, which is required for proper protein transport through the Golgi. The domain facilitates guanine nucleotide exchange on the small GTPases, ARFs (ADP ribosylation factors).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958762347   530 MANSIRNDEGAWNLALRLYQLNGFRKSEVAAHLRKNNDFSRAVAEAYLSFFQFEGQSLDRALRGFLQALVLSGETQERER 609
Cdd:smart00222   27 QEKGFLANEDPQDVADFLSKNEGLNKKAIGDYLGEHDEFNRLVLHAFVDLFDFSAKDLDQALREFLESFRLPGEAQKIDR 106

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958762347   610 ILYQFSKRFHYCNPG--AFPSVDSVHTLTCAIMLLNTDLHGQNIGKSMSCQEFVTNLNGLQDGGNFPKELLKALYWSIRS 687
Cdd:smart00222  107 LLEAFSSRYCECNPGvfSKANADAAYTLAYSLIMLNTDLHNPNVKKKMTLEDFIKNVRGSNDGEDLPREFLEELYDSIKN 186

                    ...
gi 1958762347   688 EKL 690
Cdd:smart00222  187 NEI 189

Pleckstrin homology domain; This Pleckstrin homology domain is found in some fungal species.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958762347  730 YKQGILARKMHHDADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGqwldgESLVGHMMDE------PVG---VHHSLASP 800
Cdd:pfam15410    1 YKKGIVMRKCCFESKGKKTPRGKRSWKMVYAVLKDLVLYLYKDEH-----PPESSQFEDKkslknaPVGkirLHHALATP 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 1958762347  801 ATHYTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAA 843
Cdd:pfam15410   76 APDYTKKSHVFRLQTADGAEYLFQTGSPKELQEWVDTLNYWAA 118

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 1958762347   746 KKTPWGKRGWKMFHTLLRGMVLYFLKgegqwlDGESLVGHMMDEPVGVHHSLASPATHYT--KKPHVFQLRTADWRLYLF 823
Cdd:smart00233    9 KKSGGGKKSWKKRYFVLFNSTLLYYK------SKKDKKSYKPKGSIDLSGCTVREAPDPDssKKPHCFEIKTSDRKTLLL 82

                            90       100
                    ....*....|....*....|
gi 1958762347   824 QAPTAKEMASWIARINLAAA 843
Cdd:smart00233   83 QAESEEEREKWVEALRKAIA 102

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 1958762347  724 DPTMPTYKQGILARKMHHDADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGQwlDGESLVGHMMDEPVGVHHSLASPATH 803
Cdd:cd13295      1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYG--CKKALRYESLRNAISVHHSLATKATD 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1958762347  804 YTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAATHSAPPFP 851
Cdd:cd13295     79 YTKKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSAPPLP 126

Sec7 domain; Domain named after the S. cerevisiae SEC7 gene product, which is required for proper protein transport through the Golgi. The domain facilitates guanine nucleotide exchange on the small GTPases, ARFs (ADP ribosylation factors).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958762347   530 MANSIRNDEGAWNLALRLYQLNGFRKSEVAAHLRKNNDFSRAVAEAYLSFFQFEGQSLDRALRGFLQALVLSGETQERER 609
Cdd:smart00222   27 QEKGFLANEDPQDVADFLSKNEGLNKKAIGDYLGEHDEFNRLVLHAFVDLFDFSAKDLDQALREFLESFRLPGEAQKIDR 106

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958762347   610 ILYQFSKRFHYCNPG--AFPSVDSVHTLTCAIMLLNTDLHGQNIGKSMSCQEFVTNLNGLQDGGNFPKELLKALYWSIRS 687
Cdd:smart00222  107 LLEAFSSRYCECNPGvfSKANADAAYTLAYSLIMLNTDLHNPNVKKKMTLEDFIKNVRGSNDGEDLPREFLEELYDSIKN 186

                    ...
gi 1958762347   688 EKL 690
Cdd:smart00222  187 NEI 189

Pleckstrin homology domain; This Pleckstrin homology domain is found in some fungal species.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958762347  730 YKQGILARKMHHDADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGqwldgESLVGHMMDE------PVG---VHHSLASP 800
Cdd:pfam15410    1 YKKGIVMRKCCFESKGKKTPRGKRSWKMVYAVLKDLVLYLYKDEH-----PPESSQFEDKkslknaPVGkirLHHALATP 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 1958762347  801 ATHYTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAA 843
Cdd:pfam15410   76 APDYTKKSHVFRLQTADGAEYLFQTGSPKELQEWVDTLNYWAA 118

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 1958762347  732 QGILARKMHHDADGKKTPwgKRGWKMFHTLLRGMVLYFLKGEGQWLDGESLVGHmmdEPVGVHHSLASPATHYTKKPHVF 811
Cdd:cd10571      2 EGFLERKHEWESGGKKAS--NRSWKNVYTVLRGQELSFYKDQKAAKSGITYAAE---PPLNLYNAVCEVASDYTKKKHVF 76

                           90       100       110
                   ....*....|....*....|....*....|
gi 1958762347  812 QLRTADWRLYLFQAPTAKEMASWIARINLA 841
Cdd:cd10571     77 RLKLSDGAEFLFQAKDEEEMNQWVKKISFA 106

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 1958762347   746 KKTPWGKRGWKMFHTLLRGMVLYFLKgegqwlDGESLVGHMMDEPVGVHHSLASPATHYT--KKPHVFQLRTADWRLYLF 823
Cdd:smart00233    9 KKSGGGKKSWKKRYFVLFNSTLLYYK------SKKDKKSYKPKGSIDLSGCTVREAPDPDssKKPHCFEIKTSDRKTLLL 82

                            90       100
                    ....*....|....*....|
gi 1958762347   824 QAPTAKEMASWIARINLAAA 843
Cdd:smart00233   83 QAESEEEREKWVEALRKAIA 102

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 1958762347  729 TYKQGILARK--MHHDADGKKTPWGKRGWKMFHTLLRG-MVLYFLKGEGQWLDGESLVGHMMDepvgVHHSLASPATHYT 805
Cdd:cd01230      3 VRKAGWLSVKnfLVHKKNKKVELATRRKWKKYWVCLKGcTLLFYECDERSGIDENSEPKHALF----VEGSIVQAVPEHP 78

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1958762347  806 KKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAAT 844
Cdd:cd01230     79 KKDFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACAS 117

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
                   ....*....|....*....|....*....|....*....|....*.
gi 1958762347  796 SLASPATHYTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLA 841
Cdd:cd13301     52 TITSPCLEYGKRPLVFKLTTAKGQEHFFQACSREERDAWAKDITKA 97

KIFIA and KIFIB protein pleckstrin homology (PH) domain; The kinesin-3 family motors KIFIA (Caenorhabditis elegans homolog unc-104) and KIFIB transport synaptic vesicle precursors that contain synaptic vesicle proteins, such as synaptophysin, synaptotagmin and the small GTPase RAB3A, but they do not transport organelles that contain plasma membrane proteins. They have a N-terminal motor domain, followed by a coiled-coil domain, and a C-terminal PH domain. KIF1A adopts a monomeric form in vitro, but acts as a processive dimer in vivo. KIF1B has alternatively spliced isoforms distinguished by the presence or absence of insertion sequences in the conserved amino-terminal region of the protein; this results in their different motor activities. KIF1A and KIF1B bind to RAB3 proteins through the adaptor protein mitogen-activated protein kinase (MAPK) -activating death domain (MADD; also calledDENN), which was first identified as a RAB3 guanine nucleotide exchange factor (GEF). 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
                   ....*....|....*....|....*....|....
gi 1958762347  806 KKPHVFQLRTADwRLYLFQAPTAKEMASWIARIN 839
Cdd:cd01233     67 GRPNVFAVYTPT-NSYLLQARSEKEMQDWLYAID 99