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 29243984  722 DPTMPTYKQGILARKMHHIADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGQwlDGESLVGHMVDEPVGVHHSLASPATH 801
Cdd:cd13295    1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYG--CKKALRYESLRNAISVHHSLATKATD 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 29243984  802 YTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAATHSAPPFP 849
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 29243984  722 DPTMPTYKQGILARKMHHIADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGQwlDGESLVGHMVDEPVGVHHSLASPATH 801
Cdd:cd13295    1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYG--CKKALRYESLRNAISVHHSLATKATD 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 29243984  802 YTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAATHSAPPFP 849
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 29243984     513 QSPEEGWRPSSSREKLANDIRNDkgawnLALRLYQLNGFRKSEVAAHLRKNNDFSRAVAEAYLSFFQFEGQSLDRALRGF 592
Cdd:smart00222   17 DKPKKGIQSLQEKGFLANEDPQD-----VADFLSKNEGLNKKAIGDYLGEHDEFNRLVLHAFVDLFDFSAKDLDQALREF 91

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 29243984     593 LQALVLSGETQERERILYQFSKRFHYCNPG--AFPSVDSVHTLTCAIMLLNTDLHGQNIGKSMSCQEFVTNLNGLQDGRN 670
Cdd:smart00222   92 LESFRLPGEAQKIDRLLEAFSSRYCECNPGvfSKANADAAYTLAYSLIMLNTDLHNPNVKKKMTLEDFIKNVRGSNDGED 171

                           170
                    ....*....|....*...
gi 29243984     671 FPKELLKALYWSIRSEKL 688
Cdd:smart00222  172 LPREFLEELYDSIKNNEI 189

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 29243984    728 YKQGILARKMHHIADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGqwldgESLVGHMVDE------PVG---VHHSLASP 798
Cdd:pfam15410    1 YKKGIVMRKCCFESKGKKTPRGKRSWKMVYAVLKDLVLYLYKDEH-----PPESSQFEDKkslknaPVGkirLHHALATP 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 29243984    799 ATHYTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAA 841
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 29243984     744 KKTPWGKRGWKMFHTLLRGMVLYFLKGEGQWLDGE-----SLVGHMVDEPvgvhhslasPATHYTKKPHVFQLRTADWRL 818
Cdd:smart00233    9 KKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKpkgsiDLSGCTVREA---------PDPDSSKKPHCFEIKTSDRKT 79

                            90       100
                    ....*....|....*....|...
gi 29243984     819 YLFQAPTAKEMASWIARINLAAA 841
Cdd:smart00233   80 LLLQAESEEEREKWVEALRKAIA 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 29243984  722 DPTMPTYKQGILARKMHHIADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGQwlDGESLVGHMVDEPVGVHHSLASPATH 801
Cdd:cd13295    1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYG--CKKALRYESLRNAISVHHSLATKATD 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 29243984  802 YTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAATHSAPPFP 849
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 29243984     513 QSPEEGWRPSSSREKLANDIRNDkgawnLALRLYQLNGFRKSEVAAHLRKNNDFSRAVAEAYLSFFQFEGQSLDRALRGF 592
Cdd:smart00222   17 DKPKKGIQSLQEKGFLANEDPQD-----VADFLSKNEGLNKKAIGDYLGEHDEFNRLVLHAFVDLFDFSAKDLDQALREF 91

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 29243984     593 LQALVLSGETQERERILYQFSKRFHYCNPG--AFPSVDSVHTLTCAIMLLNTDLHGQNIGKSMSCQEFVTNLNGLQDGRN 670
Cdd:smart00222   92 LESFRLPGEAQKIDRLLEAFSSRYCECNPGvfSKANADAAYTLAYSLIMLNTDLHNPNVKKKMTLEDFIKNVRGSNDGED 171

                           170
                    ....*....|....*...
gi 29243984     671 FPKELLKALYWSIRSEKL 688
Cdd:smart00222  172 LPREFLEELYDSIKNNEI 189

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 29243984    728 YKQGILARKMHHIADGKKTPWGKRGWKMFHTLLRGMVLYFLKGEGqwldgESLVGHMVDE------PVG---VHHSLASP 798
Cdd:pfam15410    1 YKKGIVMRKCCFESKGKKTPRGKRSWKMVYAVLKDLVLYLYKDEH-----PPESSQFEDKkslknaPVGkirLHHALATP 75

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 29243984    799 ATHYTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAA 841
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 29243984  730 QGILARKMHHIADGKKTPwgKRGWKMFHTLLRGMVLYFLKGEGQWLDGESLVGHmvdEPVGVHHSLASPATHYTKKPHVF 809
Cdd:cd10571    2 EGFLERKHEWESGGKKAS--NRSWKNVYTVLRGQELSFYKDQKAAKSGITYAAE---PPLNLYNAVCEVASDYTKKKHVF 76

                         90       100       110
                 ....*....|....*....|....*....|
gi 29243984  810 QLRTADWRLYLFQAPTAKEMASWIARINLA 839
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 29243984     744 KKTPWGKRGWKMFHTLLRGMVLYFLKGEGQWLDGE-----SLVGHMVDEPvgvhhslasPATHYTKKPHVFQLRTADWRL 818
Cdd:smart00233    9 KKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKpkgsiDLSGCTVREA---------PDPDSSKKPHCFEIKTSDRKT 79

                            90       100
                    ....*....|....*....|...
gi 29243984     819 YLFQAPTAKEMASWIARINLAAA 841
Cdd:smart00233   80 LLLQAESEEEREKWVEALRKAIA 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 29243984  727 TYKQGILARK--MHHIADGKKTPWGKRGWKMFHTLLRG-MVLYFLKGEGQWLDGESLVGHMVDepvgVHHSLASPATHYT 803
Cdd:cd01230    3 VRKAGWLSVKnfLVHKKNKKVELATRRKWKKYWVCLKGcTLLFYECDERSGIDENSEPKHALF----VEGSIVQAVPEHP 78

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 29243984  804 KKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLAAAT 842
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 29243984  794 SLASPATHYTKKPHVFQLRTADWRLYLFQAPTAKEMASWIARINLA 839
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 29243984  804 KKPHVFQLRTADwRLYLFQAPTAKEMASWIARIN 837
Cdd:cd01233   67 GRPNVFAVYTPT-NSYLLQARSEKEMQDWLYAID 99

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 29243984  729 KQGILARKmhHIAD-GKKTpwgKRGWKMFHTLLRGMVLYFLKGEGQWLDGESLVGH---MVDepvgVHHSLASPATHYTK 804
Cdd:cd13233    2 KQGLLNKT--KIAEnGKKL---RKNWSTSWVVLTSSHLLFYKDAKSAAKSGNPYSKpesSVD----LRGASIEWAKEKSS 72

                         90       100
                 ....*....|....*....|....*...
gi 29243984  805 KPHVFQLRTADWRLYLFQAPTAKEMASW 832
Cdd:cd13233   73 RKNVFQISTVTGTEFLLQSDNDTEIREW 100