Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768022736  38 GHVLYSGWLRKSPPEKKLRLFAWRKRWFILRRGQTSSDPDVLEYYKNDGSKKPLRTINLNLCEQldVDVTLNFNKKEIQK 117
Cdd:cd01266    2 GEVVCSGWLRKSPPEKKLRRYAWKKRWFVLRSGRLSGDPDVLEYYKNDHAKKPIRVIDLNLCEQ--VDAGLTFNKKELEN 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768022736 118 GYMFDIKTSERTFYLVAETREDMNEWVQSICQICGFRQEES 158
Cdd:cd01266   80 SYIFDIKTIDRIFYLVAETEEDMNKWVRNICDICGFNPTEE 120

Grb2-associated binding proteins 1 and 2 pleckstrin homology (PH) domain; The Gab subfamily includes several Gab proteins, Drosophila DOS and C. elegans SOC-1. They are scaffolding adaptor proteins, which possess N-terminal PH domains and a C-terminus with proline-rich regions and multiple phosphorylation sites. Following activation of growth factor receptors, Gab proteins are tyrosine phosphorylated and activate PI3K, which generates 3-phosphoinositide lipids. By binding to these lipids via the PH domain, Gab proteins remain in proximity to the receptor, leading to further signaling. While not all Gab proteins depend on the PH domain for recruitment, it is required for Gab activity. The members in this cd include the Gab1 and Gab2 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 768022736  38 GHVLYSGWLRKSPPEKKLRLFAWRKRWFILRRGQTSSDPDVLEYYKNDGSKKPLRTINLNLCEQldVDVTLNFNKKEIQK 117
Cdd:cd01266    2 GEVVCSGWLRKSPPEKKLRRYAWKKRWFVLRSGRLSGDPDVLEYYKNDHAKKPIRVIDLNLCEQ--VDAGLTFNKKELEN 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768022736 118 GYMFDIKTSERTFYLVAETREDMNEWVQSICQICGFRQEES 158
Cdd:cd01266   80 SYIFDIKTIDRIFYLVAETEEDMNKWVRNICDICGFNPTEE 120

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 768022736    40 VLYSGWLRKSPPEKKLRlfaWRKRWFILRRgqtssdpDVLEYYKNDGSK---KPLRTINLNLCEqldvdVTLNFNKKEIQ 116
Cdd:smart00233   1 VIKEGWLYKKSGGGKKS---WKKRYFVLFN-------STLLYYKSKKDKksyKPKGSIDLSGCT-----VREAPDPDSSK 65

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 768022736   117 KGYMFDIKTSER-TFYLVAETREDMNEWVQSICQIC 151
Cdd:smart00233  66 KPHCFEIKTSDRkTLLLQAESEEEREKWVEALRKAI 101

Grb2-associated binding proteins 1 and 2 pleckstrin homology (PH) domain; The Gab subfamily includes several Gab proteins, Drosophila DOS and C. elegans SOC-1. They are scaffolding adaptor proteins, which possess N-terminal PH domains and a C-terminus with proline-rich regions and multiple phosphorylation sites. Following activation of growth factor receptors, Gab proteins are tyrosine phosphorylated and activate PI3K, which generates 3-phosphoinositide lipids. By binding to these lipids via the PH domain, Gab proteins remain in proximity to the receptor, leading to further signaling. While not all Gab proteins depend on the PH domain for recruitment, it is required for Gab activity. The members in this cd include the Gab1 and Gab2 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 768022736  38 GHVLYSGWLRKSPPEKKLRLFAWRKRWFILRRGQTSSDPDVLEYYKNDGSKKPLRTINLNLCEQldVDVTLNFNKKEIQK 117
Cdd:cd01266    2 GEVVCSGWLRKSPPEKKLRRYAWKKRWFVLRSGRLSGDPDVLEYYKNDHAKKPIRVIDLNLCEQ--VDAGLTFNKKELEN 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768022736 118 GYMFDIKTSERTFYLVAETREDMNEWVQSICQICGFRQEES 158
Cdd:cd01266   80 SYIFDIKTIDRIFYLVAETEEDMNKWVRNICDICGFNPTEE 120

Grb2-associated binding protein 3 pleckstrin homology (PH) domain; The Gab subfamily includes several Gab proteins, Drosophila DOS and C. elegans SOC-1. They are scaffolding adaptor proteins, which possess N-terminal PH domains and a C-terminus with proline-rich regions and multiple phosphorylation sites. Following activation of growth factor receptors, Gab proteins are tyrosine phosphorylated and activate PI3K, which generates 3-phosphoinositide lipids. By binding to these lipids via the PH domain, Gab proteins remain in proximity to the receptor, leading to further signaling. While not all Gab proteins depend on the PH domain for recruitment, it is required for Gab activity. The members in this cd include the Gab1, Gab2, and Gab3 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 768022736  37 SGHVLYSGWLRKSPPEKKLRLFAWRKRWFILRRGQTSSDPDVLEYYKNDGSKKPLRTINLNLCEQLDvDVTLNFNKKEIQ 116
Cdd:cd13385    3 AGDVVCTGWLIKSPPERKLKRYAWRKRWFVLRRGRMSGNPDVLEYYRNNHSKKPIRVIDLSECEVLK-HSGPNFIRKEFQ 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768022736 117 KGYMFDIKTSERTFYLVAETREDMNEWVQSICQICGFRQEE 157
Cdd:cd13385   82 NNFVFIVKTTYRTFYLVAKTEEEMQVWVHNISQICNFGHLE 122

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768022736   40 VLYSGWLRKSPPEKKLRlfaWRKRWFILRRgqtssdpDVLEYYKNDG---SKKPLRTINLNLCEQLDVDVTLNFNKKeiq 116
Cdd:pfam00169   1 VVKEGWLLKKGGGKKKS---WKKRYFVLFD-------GSLLYYKDDKsgkSKEPKGSISLSGCEVVEVVASDSPKRK--- 67

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 768022736  117 kgYMFDIKTSE----RTFYLVAETREDMNEWVQSICQIC 151
Cdd:pfam00169  68 --FCFELRTGErtgkRTYLLQAESEEERKDWIKAIQSAI 104

Dual Adaptor for Phosphotyrosine and 3-Phosphoinositides Pleckstrin homology (PH) domain; DAPP1 (also known as PHISH/3' phosphoinositide-interacting SH2 domain-containing protein or Bam32) plays a role in B-cell activation and has potential roles in T-cell and mast cell function. DAPP1 promotes B cell receptor (BCR) induced activation of Rho GTPases Rac1 and Cdc42, which feed into mitogen-activated protein kinases (MAPK) activation pathways and affect cytoskeletal rearrangement. DAPP1can also regulate BCR-induced activation of extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK). DAPP1 contains an N-terminal SH2 domain and a C-terminal pleckstrin homology (PH) domain with a single tyrosine phosphorylation site located centrally. DAPP1 binds strongly to both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The PH domain is essential for plasma membrane recruitment of PI3K upon cell activation. 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 768022736  34 STRSGHVLYSGWLRKSppekklrlfaWRKRWFILRRGQtssdpdvLEYYKNDGSKKPLRTINLNLCEQLDVDvtlnfNKK 113
Cdd:cd10573    3 GSKEGYLTKLGGIVKN----------WKTRWFVLRRNE-------LKYFKTRGDTKPIRVLDLRECSSVQRD-----YSQ 60

                         90       100       110
                 ....*....|....*....|....*....|.
gi 768022736 114 EiqKGYMFDIKTSERTFYLVAETREDMNEWV 144
Cdd:cd10573   61 G--KVNCFCLVFPERTFYMYANTEEEADEWV 89

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 768022736  40 VLYSGWLRKSPPEKKlrlfAWRKRWFILRRGQtssdpdvLEYYKNDGSKKPLRTINLNlceqlDVD--VTLNFNKKEiqk 117
Cdd:cd13255    6 VLKAGYLEKKGERRK----TWKKRWFVLRPTK-------LAYYKNDKEYRLLRLIDLT-----DIHtcTEVQLKKHD--- 66

                         90       100       110
                 ....*....|....*....|....*....|...
gi 768022736 118 gYMFDIKTSERTFYLVAETREDMNEWVQSICQI 150
Cdd:cd13255   67 -NTFGIVTPARTFYVQADSKAEMESWISAINLA 98

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. 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 768022736  43 SGWLrksppeKKL--RLFAWRKRWFILRRGQtssdpdvLEYYK--NDGSKKPLRTINLN-LCEqldvdvtlnfnkkeIQK 117
Cdd:cd13282    2 AGYL------TKLggKVKTWKRRWFVLKNGE-------LFYYKspNDVIRKPQGQIALDgSCE--------------IAR 54

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768022736 118 ---GYMFDIKTSERTFYLVAETREDMNEWVQSICQICGFRQ 155
Cdd:cd13282   55 aegAQTFEIVTEKRTYYLTADSENDLDEWIRVIQNVLRRQA 95

Tandem PH-domain-containing proteins 1 and 2 Pleckstrin homology (PH) domain, C-terminal repeat; The binding of TAPP1 (also called PLEKHA1/pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1) and 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). TAPP1 and TAPP2 contain 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. 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 768022736  36 RSGHVLYSGWLRKSppekklrlfaWRKRWFILrrgqtssDPDVLEYYKNDGSKKPLRTINLNlcEQLDVDVTLNfnKKEI 115
Cdd:cd13271   10 KSGYCVKQGAVRKN----------WKRRFFIL-------DDNTISYYKSETDKEPLRTIPLR--EVLKVHECLV--KSLL 68

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 768022736 116 QKGYMFDIKTSERTFYLVAETREDMNEWVQSICQIC 151
Cdd:cd13271   69 MRDNLFEIITTSRTFYIQADSPEEMHSWIKAISGAI 104

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 1; ARAP proteins (also called centaurin delta) are phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating proteins that modulate actin cytoskeleton remodeling by regulating ARF and RHO family members. They bind phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding. There are 3 mammalian ARAP proteins: ARAP1, ARAP2, and ARAP3. All ARAP proteins contain a N-terminal SAM (sterile alpha motif) domain, 5 PH domains, an ArfGAP domain, 2 ankyrin domain, A RhoGap domain, and a Ras-associating domain. This hierarchy contains the first PH domain in ARAP. 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 768022736  43 SGWLRKSPPEKKLRLfaWRKRWFILrrgqtssDPDVLEYYKNDGSKKPLRTINLNlceQLDVDVTLNFNKkeiqkgymFD 122
Cdd:cd13253    3 SGYLDKQGGQGNNKG--FQKRWVVF-------DGLSLRYFDSEKDAYSKRIIPLS---AISTVRAVGDNK--------FE 62

                         90       100
                 ....*....|....*....|....
gi 768022736 123 IKTSERTFYLVAETREDMNEWVQS 146
Cdd:cd13253   63 LVTTNRTFVFRAESDDERNLWCST 86

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 768022736  35 TRSGHVLYSGWLRK---SPpekkLRLfaWRKRWFILRRGqtssdpdVLEYYKNDGSKKPLRTINLnlceqldvdvtLNFN 111
Cdd:cd13248    2 DPNAPVVMSGWLHKqggSG----LKN--WRKRWFVLKDN-------CLYYYKDPEEEKALGSILL-----------PSYT 57

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 768022736 112 ------KKEIQKGYMFDI-KTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd13248   58 ispappSDEISRKFAFKAeHANMRTYYFAADTAEEMEQWMNAM 100

Arabidopsis thaliana Pleckstrin homolog (PH) 1 (AtPH1) PH domain; AtPH1 is expressed in all plant tissue and is proposed to be the plant homolog of human pleckstrin. Pleckstrin consists of two PH domains separated by a linker region, while AtPH has a single PH domain with a short N-terminal extension. AtPH1 binds PtdIns3P specifically and is thought to be an adaptor molecule since it has no obvious catalytic functions. 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 768022736  43 SGWLRKSPPEKKlrlfAWRKRWFILRRGQ--TSSDPDVLEYykndgsKKPLRTINLNLCeqldvdVTLNFNKKEIQKGYM 120
Cdd:cd13276    2 AGWLEKQGEFIK----TWRRRWFVLKQGKlfWFKEPDVTPY------SKPRGVIDLSKC------LTVKSAEDATNKENA 65

                         90       100
                 ....*....|....*....|....*..
gi 768022736 121 FDIKTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd13276   66 FELSTPEETFYFIADNEKEKEEWIGAI 92

Myosin X-like Pleckstrin homology (PH) domain, repeat 3; MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C-terminus. The first PH domain in the MyoX tail is a split-PH domain, interupted by the second PH domain such that PH 1a and PH 1b flanks PH 2. The third PH domain (PH 3) follows the PH 1b domain. This cd contains the third MyoX PH repeat. PLEKHH3/Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) member 3 is also part of this CD and like MyoX contains a FERM domain, a MyTH4 domain, and a single PH domain. Not much is known about the function of PLEKHH3. 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 768022736  40 VLYSGWLRKSPPEKKLRlfAW---RKRWFILRRgqtssdpDVLEYYKN-DGSKKPLRTINLN-LCEQLDVDvtlnfNKKE 114
Cdd:cd13297   13 VIERGWLYKEGGKGGAR--GNltkKKRWFVLTG-------NSLDYYKSsEKNSLKLGTLVLNsLCSVVPPD-----EKMA 78

                         90       100       110
                 ....*....|....*....|....*....|....
gi 768022736 115 IQKGY-MFDIKTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd13297   79 KETGYwTFTVHGRKHSFRLYTKLQEEAMRWVNAI 112

Set binding factor 1 (also called Human MTMR5) Pleckstrin Homology (PH) domain; Sbf1 is a myotubularin-related pseudo-phosphatase. Both Sbf1 and myotubularin interact with the SET domains of Hrx and other epigenetic regulatory proteins, but Sbf1 lacks phosphatase activity due to several amino acid changes in its structurally preserved catalytic pocket. It contains pleckstrin (PH), GEF, and myotubularin homology domains that are thought to be responsible for signaling and growth control. Sbf1 functions as an inhibitor of cellular growth. The N-terminal GEF homology domain serves to inhibit the transforming effects of Sbf1. 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 768022736  42 YSGWLRKsppeKKLRLFAWRKRWFIL--RRGQtssdpdvLEYYKNDGSKKPLRTINLNLCEQLDVDVTLNFNKKEIQKGY 119
Cdd:cd01235    5 HEGYLYK----RGALLKGWKQRWFVLdsTKHQ-------LRYYESREDTKCKGFIDLAEVESVTPATPIIGAPKRADEGA 73

                         90       100
                 ....*....|....*....|....*...
gi 768022736 120 MFDIKTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd01235   74 FFDLKTNKRVYNFCAFDAESAQQWIEKI 101

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 768022736  40 VLYSGWLRKSPPEKKLRLFAWRKRWFILRRGqtssdpdVLEYYKNDGSKKPLRTINLNlceQLDVDVTLNFNKKEiQKGY 119
Cdd:cd13266    1 VIKAGYLEKRRKDHSFFGSEWQKRWCAISKN-------VFYYYGSDKDKQQKGEFAIN---GYDVRMNPTLRKDG-KKDC 69

                         90       100
                 ....*....|....*....|....*....
gi 768022736 120 MFDIKT-SERTFYLVAETREDMNEWVQSI 147
Cdd:cd13266   70 CFELVCpDKRTYQFTAASPEDAEDWVDQI 98

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 2; 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 second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768022736  37 SGHVLYSGWLRKSPPEKKlrlfAWRKRWFILRrgqtsSDPDVLEYYKNDGSKKPLRTINLNLCEQLDVDVTLNFNKKEIQ 116
Cdd:cd13302    4 RGIIVKQGCLLKQGHRRK----NWKVRKFVLR-----DDPAYLHYYDPAKGEDPLGAIHLRGCVVTAVEDNSNPRKGSVE 74

                         90       100       110
                 ....*....|....*....|....*....|..
gi 768022736 117 kGYMFDIKTSERT-FYLVAETREDMNEWVQSI 147
Cdd:cd13302   75 -GNLFEIITADEVhYYLQAATPAERTEWIKAI 105

SH3 domain-binding protein 2 Pleckstrin homology (PH) domain; SH3BP2 (the gene that encodes the adaptor protein 3BP2), HD, ITU, IT10C3, and ADD1 are located near the Huntington's Disease Gene on Human Chromosome 4pl6.3. SH3BP2 lies in a region that is often missing in individuals with Wolf-Hirschhorn syndrome (WHS). Gain of function mutations in SH3BP2 causes enhanced B-cell antigen receptor (BCR)-mediated activation of nuclear factor of activated T cells (NFAT), resulting in a rare, genetic disorder called cherubism. This results in an increase in the signaling complex formation with Syk, phospholipase C-gamma2 (PLC-gamma2), and Vav1. It was recently discovered that Tankyrase regulates 3BP2 stability through ADP-ribosylation and ubiquitylation by the E3-ubiquitin ligase. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the Src, Syk, and Vav signaling pathways. SH3BP2 is also a potential negative regulator of the abl oncogene. 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 768022736  40 VLYSGWLRKSPPEKKLrLFAWRKRWFILRRGqtssdpdVLEYYKNDGSKKPLRTINLNlceqldvdvtlNFN---KKEIQ 116
Cdd:cd13308    9 VIHSGTLTKKGGSQKT-LQNWQLRYVIIHQG-------CVYYYKNDQSAKPKGVFSLN-----------GYNrraAEERT 69

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 768022736 117 KGYMFDIK-----TSERTFYLVAETREDMNEWVQSI 147
Cdd:cd13308   70 SKLKFVFKiihlsPDHRTWYFAAKSEDEMSEWMEYI 105

Rho GTPase activating protein 2 Pleckstrin homology (PH) domain; RhoGAP2 (also called RhoGap22 or ArhGap22) are involved in cell polarity, cell morphology and cytoskeletal organization. They activate a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt, and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues resulting in regulation of cell motility. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) 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 768022736  38 GHVLYSGWLRKSPPEKKlrlfAWRKRWFILRrgqtssdPDVLEYYKNDGSKKPLRTINLNlCEQLDvdvTLNFNKKEIQK 117
Cdd:cd13378    1 EGVLKAGWLKKQRSIMK----NWQQRWFVLR-------GDQLFYYKDEEETKPQGCISLQ-GSQVN---ELPPNPEEPGK 65

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 768022736 118 gYMFDI-----------KTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd13378   66 -HLFEIlpggagdrekvPMNHEAFLLMANSQSDMEDWVKAI 105

Switch-associated protein-70 Pleckstrin homology (PH) domain; SWAP-70 (also called Differentially expressed in FDCP 6/DEF-6 or IRF4-binding protein) functions in cellular signal transduction pathways (in conjunction with Rac), regulates cell motility through actin rearrangement, and contributes to the transformation and invasion activity of mouse embryo fibroblasts. Metazoan SWAP-70 is found in B lymphocytes, mast cells, and in a variety of organs. Metazoan SWAP-70 contains an N-terminal EF-hand motif, a centrally located PH domain, and a C-terminal coiled-coil domain. The PH domain of Metazoan SWAP-70 contains a phosphoinositide-binding site and a nuclear localization signal (NLS), which localize SWAP-70 to the plasma membrane and nucleus, respectively. The NLS is a sequence of four Lys residues located at the N-terminus of the C-terminal a-helix; this is a unique characteristic of the Metazoan SWAP-70 PH domain. The SWAP-70 PH domain binds PtdIns(3,4,5)P3 and PtdIns(4,5)P2 embedded in lipid bilayer vesicles. There are additional plant SWAP70 proteins, but these are not included in this hierarchy. Rice SWAP70 (OsSWAP70) exhibits GEF activity toward the its Rho GTPase, OsRac1, and regulates chitin-induced production of reactive oxygen species and defense gene expression in rice. Arabidopsis SWAP70 (AtSWAP70) plays a role in both PAMP- and effector-triggered immunity. Plant SWAP70 contains both DH and PH domains, but their arrangement is the reverse of that in typical DH-PH-type Rho GEFs, wherein the DH domain is flanked by a C-terminal 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 768022736  38 GHVLYSGWLRKsppeKKLRLFAWRKRWFILRrgqtssdPDVLEYYKNDGSKKPLRTINLNlcEQLDVDVTLNFNKKEiqk 117
Cdd:cd13273    6 LDVIKKGYLWK----KGHLLPTWTERWFVLK-------PNSLSYYKSEDLKEKKGEIALD--SNCCVESLPDREGKK--- 69

                         90       100       110
                 ....*....|....*....|....*....|
gi 768022736 118 gYMFDIKTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd13273   70 -CRFLVKTPDKTYELSASDHKTRQEWIAAI 98

Ras-specific guanine nucleotide-releasing factors 1 and 2 Pleckstrin homology (PH) domain; RasGRF1 (also called GRF1; CDC25Mm/Ras-specific nucleotide exchange factor CDC25; GNRP/Guanine nucleotide-releasing protein) and RasGRF2 (also called GRF2; Ras guanine nucleotide exchange factor 2) are a family of guanine nucleotide exchange factors (GEFs). They both promote the exchange of Ras-bound GDP by GTP, thereby regulating the RAS signaling pathway. RasGRF1 and RasGRF2 form homooligomers and heterooligomers. GRF1 has 3 isoforms and GRF2 has 2 isoforms. The longest isoforms of RasGRF1 and RasGRF2 contain the following domains: a Rho-GEF domain sandwiched between 2 PH domains, IQ domains, a REM (Ras exchanger motif) domain, and a Ras-GEF domainwhich gives them the capacity to activate both Ras and Rac GTPases in response to signals from a variety of neurotransmitter receptors. Their IQ domains allow them to act as calcium sensors to mediate the actions of NMDA-type and calcium-permeable AMPA-type glutamate receptors. GRF1 also mediates the action of dopamine receptors that signal through cAMP. GRF1 and GRF2 play strikingly different roles in regulating MAP kinase family members, neuronal synaptic plasticity, specific forms of learning and memory, and behavioral responses to psychoactive drugs. 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 768022736  60 WRKRWFILRRgqtssdpDVLEYYKNDGSKKPLRTINLN--LCEQLDVDVTLNFNKKEIQKGYMFDI---KTSERTFYLVA 134
Cdd:cd13261   21 WHERWFALYQ-------NLLFYFENESSSRPSGLYLLEgcYCERLPTPKGALKGKDHLEKQHYFTIsfrHENQRQYELRA 93

                         90       100
                 ....*....|....*....|
gi 768022736 135 ETREDMNEWVQSICQiCGFR 154
Cdd:cd13261   94 ETESDCDEWVEAIKQ-ASFN 112

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768022736   44 GWLRKSPPEkklrlfAWRKRWFILRRgqtssdPDVLEYYKNDGSKKPLRTINLNLCEQ--LDVDVTLN--------FNKK 113
Cdd:pfam15413   3 GYLKKKGPK------TWKHRWFAVLR------NGVLFYYKSEKMKVVKHVIVLSNYIVgkLGTDIISGalfkidniRSET 70

                          90       100       110
                  ....*....|....*....|....*....|....
gi 768022736  114 EIQKgyMFDIKTSERTFYLVAETREDMNEWVQSI 147
Cdd:pfam15413  71 SDDL--LLEISTETKIFFLYGDNNEETYEWVEAL 102

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 768022736  38 GHVLYSGWLRKSPPEKKLRLFAWRKRWFILRRgqtssdpDVLEYYKNDGSKKPLRTINLNlceqldvDVTLNfNKKEIQK 117
Cdd:cd01260   11 GRGDCQGWLWKKKEAKSFFGQKWKKYWFVLKG-------SSLYWYSNQQDEKAEGFINLP-------DFKIE-RASECKK 75

                         90       100       110
                 ....*....|....*....|....*....|.
gi 768022736 118 GYMFDI-KTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd01260   76 KYAFKAcHPKIKTFYFAAENLDDMNKWLSKL 106

Pleckstrin homology-like domain-containing family B member 2 pleckstrin homology (PH) domain; PHLDB2 (also called LL5beta) and PHLDB1 (also called LL5alpha) are cytoskeleton- and membrane-associated proteins. PHLDB2 has been identified as a key component of the synaptic podosomes that play an important role in in postsynaptic maturation. Both are large proteins containing an N-terminal pleckstrin (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 768022736  56 RLFAWRKRWFILRRgqtssDPDVLEYYKNDGSKKPLRTINLNLCEQLDVDvTLNFNKKEIQKGYMFDIKTSERTFYLVAE 135
Cdd:cd14673   15 KIKTWKKRWFVFDR-----NKRTLSYYVDKHEKKLKGVIYFQAIEEVYYD-HLRSAAKSPNPALTFCVKTHDRLYYMVAP 88

                         90
                 ....*....|..
gi 768022736 136 TREDMNEWVQSI 147
Cdd:cd14673   89 SPEAMRIWMDVI 100

Plant Oxysterol binding protein related protein Pleckstrin homology (PH) domain; Plant ORPs contain a N-terminal PH domain and a C-terminal OSBP-related domain. Not much is known about its specific function in plants to date. Members here include: Arabidopsis, spruce, and petunia. Oxysterol binding proteins are a multigene family that is conserved in yeast, flies, worms, mammals and plants. In general OSBPs and ORPs have been found to be involved in the transport and metabolism of cholesterol and related lipids in eukaryotes. They all contain a C-terminal oxysterol binding domain, and most contain an N-terminal PH domain. OSBP PH domains bind to membrane phosphoinositides and thus likely play an important role in intracellular targeting. They are members of the oxysterol binding protein (OSBP) family which includes OSBP, OSBP-related proteins (ORP), Goodpasture antigen binding protein (GPBP), and Four phosphate adaptor protein 1 (FAPP1). They have a wide range of purported functions including sterol transport, cell cycle control, pollen development and vessicle transport from Golgi recognize both PI lipids and ARF 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 768022736  60 WRKRWFILRRGqtssdpdVLEYYKNDGSK--KPLRTINLNLCeqldvdvTLNFNKKEIQKGYMFdikTSERTFYLVAETR 137
Cdd:cd13294   15 WRSRWFVLQDG-------VLSYYKVHGPDkvKPSGEVHLKVS-------SIRESRSDDKKFYIF---TGTKTLHLRAESR 77

                         90
                 ....*....|
gi 768022736 138 EDMNEWVQSI 147
Cdd:cd13294   78 EDRAAWLEAL 87

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768022736  35 TRSGHVLYSGWL-RKSPPEKklrlfAWRKRWFILRRgqtssdPDVLEYYKNDGSKKpLRTINLNLCEqldVDVTLNFnKK 113
Cdd:cd01233    1 PKSPVVSKRGYLlFLEDATD-----GWVRRWVVLRR------PYLHIYSSEKDGDE-RGVINLSTAR---VEYSPDQ-EA 64

                         90       100       110
                 ....*....|....*....|....*....|....
gi 768022736 114 EIQKGYMFDIKTSERTFYLVAETREDMNEWVQSI 147
Cdd:cd01233   65 LLGRPNVFAVYTPTNSYLLQARSEKEMQDWLYAI 98

GTPase activating protein 1 m pleckstrin homology (PH) domain; GAP1(m) (also called RASA2/RAS p21 protein activator (GTPase activating protein) 2) is a member of the GAP1 family of GTPase-activating proteins, along with RASAL1, GAP1(IP4BP), and CAPRI. With the notable exception of GAP1(m), they all possess an arginine finger-dependent GAP activity on the Ras-related protein Rap1. GAP1(m) contains two C2 domains, a PH domain, a RasGAP domain, and a BTK domain. Its C2 domains, like those of GAP1IP4BP, do not contain the C2 motif that is known to be required for calcium-dependent phospholipid binding. GAP1(m) is regulated by the binding of its PH domains to phophoinositides, PIP3 (phosphatidylinositol 3,4,5-trisphosphate). It suppresses RAS, enhancing the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, allowing control of cellular proliferation and differentiation. GAP1(m) binds inositol tetrakisphosphate (IP4). 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 768022736  60 WRKRWFILrrgqTSSDpdvLEYYKNDGsKKPLRTI---NLNLCEQLDVDvtlNFNKKEiqkgyMFDIKTSERTFYLVAET 136
Cdd:cd13370   37 FKKRWFCL----TSRE---LTYHKQKG-KEAIFTIpvkNILAVEKLEES---AFNKKN-----MFQVIHSEKPLYVQANN 100

                         90
                 ....*....|....
gi 768022736 137 REDMNEWVQSICQI 150
Cdd:cd13370  101 CVEANEWIEVLSRV 114

Fungal proteins Pleckstrin homology (PH) domain, repeat 2; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents the second PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768022736  40 VLYSGWLRKsppEKKLRLFAWRKRWFILRrgqtssdPDVLEYYKNDGSKKPLRTINLN-LCEQLDVDVtLNFNKKeiqkg 118
Cdd:cd13299    6 VIEQGYLQV---LKKKGVNQWKKYWLVLR-------NRSLSFYKDQSEYSPVKIIPIDdIIDVVELDP-LSKSKK----- 69