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 1907188433  768 DPNAAVYKSGFLARKIHADMDGKKTPRGKRGWKTFYAVLKGTVLYLQKDEYKPEKSLSDEDLKNAVSVHHALASKATDYE 847
Cdd:cd13295      1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYGCKKALRYESLRNAISVHHSLATKATDYT 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 1907188433  848 KKPNVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAAVFSAPPFP 893
Cdd:cd13295     81 KKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSAPPLP 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 1907188433  768 DPNAAVYKSGFLARKIHADMDGKKTPRGKRGWKTFYAVLKGTVLYLQKDEYKPEKSLSDEDLKNAVSVHHALASKATDYE 847
Cdd:cd13295      1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYGCKKALRYESLRNAISVHHSLATKATDYT 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 1907188433  848 KKPNVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAAVFSAPPFP 893
Cdd:cd13295     81 KKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSAPPLP 126

Sec7 domain; The Sec7 domain is a guanine-nucleotide-exchange-factor (GEF) for the pfam00025 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907188433  573 AKRLAKRLYHLDRFKRSDVAKHLGKNNEFSKLVAEEYLKFFDFTGMTLDQSLRYFLKAFSLVGETQERERVLIHFSNRYF 652
Cdd:pfam01369   33 PESIAKFLFETPGLDKKAIGEYLGKPDEFNIEVLKAFVDLFDFKGLRIDEALRLFLESFRLPGEAQKIDRIMEAFAERYY 112

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907188433  653 SCNPDTITSKDGVHCLTCAMMLLNTDLHGHNIGKKMTCQEFITNLQGVNEGGDFSKDLLKALYNSIKNEKL 723
Cdd:pfam01369  113 EQNPGVFANADAAYVLAYSIIMLNTDLHNPNVKKKMTLEDFIRNLRGINDGKDFPDEYLEEIYDSIKKNEI 183

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907188433  774 YKSGFLARKIHADMDGKKTPRGKRGWKTFYAVLKGTVLYLQKDEYKPEKSLSDE--DLKNA----VSVHHALASKATDYE 847
Cdd:pfam15410    1 YKKGIVMRKCCFESKGKKTPRGKRSWKMVYAVLKDLVLYLYKDEHPPESSQFEDkkSLKNApvgkIRLHHALATPAPDYT 80

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 1907188433  848 KKPNVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAA 885
Cdd:pfam15410   81 KKSHVFRLQTADGAEYLFQTGSPKELQEWVDTLNYWAA 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 1907188433   773 VYKSGFLArkihadmdgKKTPRGKRGWKTFYAVLKGTVLYLqkdeYKPEKSLSDEDLKNAVSVHHALASKATDYE--KKP 850
Cdd:smart00233    1 VIKEGWLY---------KKSGGGKKSWKKRYFVLFNSTLLY----YKSKKDKKSYKPKGSIDLSGCTVREAPDPDssKKP 67

                            90       100       110
                    ....*....|....*....|....*....|....*
gi 1907188433   851 NVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAA 885
Cdd:smart00233   68 HCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 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 1907188433  768 DPNAAVYKSGFLARKIHADMDGKKTPRGKRGWKTFYAVLKGTVLYLQKDEYKPEKSLSDEDLKNAVSVHHALASKATDYE 847
Cdd:cd13295      1 DPNAVEYKKGYLMRKCCADPDGKKTPFGKRGWKMFYATLKGLVLYLHKDEYGCKKALRYESLRNAISVHHSLATKATDYT 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 1907188433  848 KKPNVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAAVFSAPPFP 893
Cdd:cd13295     81 KKPHVFRLRTADWREYLFQASDTKEMQSWIEAINLVAAAFSAPPLP 126

Sec7 domain; The Sec7 domain is a guanine-nucleotide-exchange-factor (GEF) for the pfam00025 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907188433  573 AKRLAKRLYHLDRFKRSDVAKHLGKNNEFSKLVAEEYLKFFDFTGMTLDQSLRYFLKAFSLVGETQERERVLIHFSNRYF 652
Cdd:pfam01369   33 PESIAKFLFETPGLDKKAIGEYLGKPDEFNIEVLKAFVDLFDFKGLRIDEALRLFLESFRLPGEAQKIDRIMEAFAERYY 112

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1907188433  653 SCNPDTITSKDGVHCLTCAMMLLNTDLHGHNIGKKMTCQEFITNLQGVNEGGDFSKDLLKALYNSIKNEKL 723
Cdd:pfam01369  113 EQNPGVFANADAAYVLAYSIIMLNTDLHNPNVKKKMTLEDFIRNLRGINDGKDFPDEYLEEIYDSIKKNEI 183

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907188433  774 YKSGFLARKIHADMDGKKTPRGKRGWKTFYAVLKGTVLYLQKDEYKPEKSLSDE--DLKNA----VSVHHALASKATDYE 847
Cdd:pfam15410    1 YKKGIVMRKCCFESKGKKTPRGKRSWKMVYAVLKDLVLYLYKDEHPPESSQFEDkkSLKNApvgkIRLHHALATPAPDYT 80

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 1907188433  848 KKPNVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAA 885
Cdd:pfam15410   81 KKSHVFRLQTADGAEYLFQTGSPKELQEWVDTLNYWAA 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 1907188433  777 GFLARKIHADMDGKKTPrgKRGWKTFYAVLKGTVLYLqkdeYKPEKSLSDEDLKNA---VSVHHALASKATDYEKKPNVF 853
Cdd:cd10571      3 GFLERKHEWESGGKKAS--NRSWKNVYTVLRGQELSF----YKDQKAAKSGITYAAeppLNLYNAVCEVASDYTKKKHVF 76

                           90       100
                   ....*....|....*....|....*...
gi 1907188433  854 KLKTADWRVLLFQTQSPEEMQGWINKIN 881
Cdd:cd10571     77 RLKLSDGAEFLFQAKDEEEMNQWVKKIS 104

ARHGAP21 and related proteins pleckstrin homology (PH) domain; ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with a RhoGAP domain. These proteins functions as a GTPase-activating protein (GAP) for RHOA and CDC42. ARHGAP21 controls the Arp2/3 complex and F-actin dynamics at the Golgi complex by regulating the activity of the small GTPase Cdc42. It is recruited to the Golgi by to GTPase, ARF1, through its PH domain and its helical motif. It is also required for CTNNA1 recruitment to adherens junctions. ARHGAP21 and it related proteins all contains a PH domain and a RhoGAP domain. Some of the members have additional N-terminal domains including PDZ, SH3, and SPEC. The ARHGAP21 PH domain interacts with the GTPbound forms of both ARF1 and ARF6 ARF-binding domain/ArfBD. The members here include: ARHGAP15, ARHGAP21, and ARHGAP23. 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 1907188433  774 YKSGFLARKIHADMDGKKTPRgkRGWKTFYAVLKGTVLYLQKDEYKPEKSLSDE-DLKNAVSVHHALASKATDYEKKPNV 852
Cdd:cd01253      1 AREGWLHYKQIVTDKGKRVSD--RSWKQAWAVLRGHSLYLYKDKREQTPALSIElGSEQRISIRGCIVDIAYSYTKRKHV 78

                           90       100
                   ....*....|....*....|....*...
gi 1907188433  853 FKLKTADWRVLLFQTQSPEEMQGWINKI 880
Cdd:cd01253     79 FRLTTSDFSEYLFQAEDRDDMLGWIKAI 106

Pleckstrin homology (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 1907188433  775 KSGFLArkihadmdgKKTPRGKRGWKTFYAVLKGTVLYLqkdeYKPEKSLSDEdLKNAVSVHHALASKATDYEKKPNVFK 854
Cdd:cd00821      1 KEGYLL---------KRGGGGLKSWKKRWFVLFEGVLLY----YKSKKDSSYK-PKGSIPLSGILEVEEVSPKERPHCFE 66

                           90       100
                   ....*....|....*....|....*.
gi 1907188433  855 LKTADWRVLLFQTQSPEEMQGWINKI 880
Cdd:cd00821     67 LVTPDGRTYYLQADSEEERQEWLKAL 92

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 1907188433  772 AVYKSGFLARK--IHADMDGKKTPRGKRGWKTFYAVLKG-TVLYLQKDEYKPEKSLSDEdlKNAVSVHHALASKATDYEK 848
Cdd:cd01230      2 AVRKAGWLSVKnfLVHKKNKKVELATRRKWKKYWVCLKGcTLLFYECDERSGIDENSEP--KHALFVEGSIVQAVPEHPK 79

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1907188433  849 KPNVFKLKTADWRVLLFQTQSPEEMQGWINKINCVAA 885
Cdd:cd01230     80 KDFVFCLSNSFGDAYLFQATSQTELENWVTAIHSACA 116

Tandem PH-domain-containing protein 2 Pleckstrin homology (PH) domain; The binding of TAPP2 (also called PLEKHA2) adaptors to PtdIns(3,4)P(2), but not PI(3,4, 5)P3, function as negative regulators of insulin and PI3K signalling pathways (i.e. TAPP/utrophin/syntrophin complex). TAPP2 contains two sequential PH domains in which the C-terminal PH domain specifically binds PtdIns(3,4)P2 with high affinity. The N-terminal PH domain does not interact with any phosphoinositide tested. They also contain a C-terminal PDZ-binding motif that interacts with several PDZ-binding proteins, including PTPN13 (known previously as PTPL1 or FAP-1) as well as the scaffolding proteins MUPP1 (multiple PDZ-domain-containing protein 1), syntrophin and utrophin. The members here are most sequence similar to TAPP2 proteins, but may not be actual TAPP2 proteins. 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 1907188433  770 NAAVYKSGFLArkihadmdgKKTPRGKRgWKTFYAVLKGTVL--YLQKDEYKPEKSLSDEDLKNAVSVhhalaskatDYE 847
Cdd:cd13255      3 SEAVLKAGYLE---------KKGERRKT-WKKRWFVLRPTKLayYKNDKEYRLLRLIDLTDIHTCTEV---------QLK 63

                           90       100       110
                   ....*....|....*....|....*....|....
gi 1907188433  848 KKPNVFKLKTADwRVLLFQTQSPEEMQGWINKIN 881
Cdd:cd13255     64 KHDNTFGIVTPA-RTFYVQADSKAEMESWISAIN 96

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. 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 1907188433  768 DPNAAVYKSGFLARkihadMDGKktprGKRGWKTFYAVLKGTVLYLQKDEYKpEKSLSDEDLKNaVSVHHALASKATdye 847
Cdd:cd13248      2 DPNAPVVMSGWLHK-----QGGS----GLKNWRKRWFVLKDNCLYYYKDPEE-EKALGSILLPS-YTISPAPPSDEI--- 67

                           90       100       110
                   ....*....|....*....|....*....|....
gi 1907188433  848 KKPNVFKLKTADWRVLLFQTQSPEEMQGWINKIN 881
Cdd:cd13248     68 SRKFAFKAEHANMRTYYFAADTAEEMEQWMNAMS 101

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from insects, spiders, mollusks, and nematodes. 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 1907188433  790 KKTPRGKrgWKTFYAVLKGTVLYLQKDEykpekslsdEDLKNAVSVHHA--LASKATDYEKKPNVFKL-KTAdwRVLLFQ 866
Cdd:cd13326     11 KGKGGGK--WAKRWFVLKGSNLYGFRSQ---------ESTKADCVIFLPgfTVSPAPEVKSRKYAFKVyHTG--TVFYFA 77

                           90
                   ....*....|....
gi 1907188433  867 TQSPEEMQGWINKI 880
Cdd:cd13326     78 AESQEDMKKWLDLL 91

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and, with the exception of CNK3, a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from mammals, chickens, amphibians, fish, and crustacea. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907188433  784 HADMDG----KKTPRGKRG--WKTFYAVLKGTVLYLQKDEykpekslSDEDLKNAVSVHHALASKATDYEKKpNVFKLKT 857
Cdd:cd01260     12 RGDCQGwlwkKKEAKSFFGqkWKKYWFVLKGSSLYWYSNQ-------QDEKAEGFINLPDFKIERASECKKK-YAFKACH 83

                           90       100
                   ....*....|....*....|....
gi 1907188433  858 ADWRVLLFQTQSPEEMQGWINKIN 881
Cdd:cd01260     84 PKIKTFYFAAENLDDMNKWLSKLN 107

Pleckstrin homology domain-containing family O Pleckstrin homology domain; The PLEKHO family members are PLEKHO1 (also called CKIP-1/Casein kinase 2-interacting protein 1/CK2-interacting protein 1) and PLEKHO2 (PLEKHQ1/PH domain-containing family Q member 1). They both contain a single PH domain. PLEKHO1 acts as a scaffold protein that functions in plasma membrane recruitment, transcriptional activity modulation, and posttranscriptional modification regulation. As an adaptor protein it is involved in signaling pathways, apoptosis, differentiation, cytoskeleton, and bone formation. Not much is know about PLEKHO2. 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 1907188433  790 KKTPRGKRG-WKTFYAVLKGTVLYLQKDEYKpEKSLSDEDLKNAVSVHHALASKatdyeKKPNVFKL--------KTADw 860
Cdd:cd13317     12 KKSSGGLLGiWKDRYVVLKGTQLLVYEKEEK-VFDLEDYELCEYLRCSKSRASK-----KNKSRFTLirskqpgnKAPD- 84

                           90
                   ....*....|....*...
gi 1907188433  861 rvLLFQTQSPEEMQGWIN 878
Cdd:cd13317     85 --LKFQAVSPEEKESWIN 100

Src kinase-associated phosphoprotein family Pleckstrin homology (PH) domain; Skap adaptor proteins couple receptors to cytoskeletal rearrangements. Src kinase-associated phosphoprotein of 55 kDa (Skap55)/Src kinase-associated phosphoprotein 1 (Skap1), Skap2, and Skap-homology (Skap-hom) have an N-terminal coiled-coil conformation, a central PH domain and a C-terminal SH3 domain. Their PH domains bind 3'-phosphoinositides as well as directly affecting targets such as in Skap55 where it directly affecting integrin regulation by ADAP and NF-kappaB activation or in Skap-hom where the dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch that controls ruffle formation. PH domains are only found in eukaryotes. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. 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 1907188433  773 VYKSGFLARKihadmdGKKTPRGKRGWKTFYAVLKGTVLYLqkdeYKPEKslsDEDLKNAVSVHHALASKATDYEKKPN- 851
Cdd:cd13266      1 VIKAGYLEKR------RKDHSFFGSEWQKRWCAISKNVFYY----YGSDK---DKQQKGEFAINGYDVRMNPTLRKDGKk 67

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1907188433  852 --VFKLKTADWRVLLFQTQSPEEMQGWINKINCVAAVFS 888
Cdd:cd13266     68 dcCFELVCPDKRTYQFTAASPEDAEDWVDQISFILQDLS 106