Insulin receptor substrate (IRS) pleckstrin homology (PH) domain; Insulin receptor substrate (IRS) molecules are mediators in insulin signaling and play a role in maintaining basic cellular functions such as growth and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. IRS molecules have an N-terminal PH domain, followed by an IRS-like PTB domain which has a PH-like fold. 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.cytoskeletal associated molecules, and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189  13 SDVRKVGYLRKPKSMHKRFFVLRAASESGPARLEYYENEKKWRHKsGAPKRSIPLESCFNINKRADSKNKHLVALYTKDE 92
Cdd:cd01257    1 TDVRKSGYLKKLKTMRKRYFVLRAESHGGPARLEYYENEKKFRRN-AEPKRVIPLSSCFNINKRADAKHKHLIALYTKDE 79

                         90       100
                 ....*....|....*....|....*..
gi 686616189  93 HFAIAADSEPEQESWYQALLQLHNRAK 119
Cdd:cd01257   80 CFGLVAESEEEQDEWYQALLELQRPAR 106

Insulin receptor substrate (IRS) pleckstrin homology (PH) domain; Insulin receptor substrate (IRS) molecules are mediators in insulin signaling and play a role in maintaining basic cellular functions such as growth and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. IRS molecules have an N-terminal PH domain, followed by an IRS-like PTB domain which has a PH-like fold. 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.cytoskeletal associated molecules, and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189  13 SDVRKVGYLRKPKSMHKRFFVLRAASESGPARLEYYENEKKWRHKsGAPKRSIPLESCFNINKRADSKNKHLVALYTKDE 92
Cdd:cd01257    1 TDVRKSGYLKKLKTMRKRYFVLRAESHGGPARLEYYENEKKFRRN-AEPKRVIPLSSCFNINKRADAKHKHLIALYTKDE 79

                         90       100
                 ....*....|....*....|....*..
gi 686616189  93 HFAIAADSEPEQESWYQALLQLHNRAK 119
Cdd:cd01257   80 CFGLVAESEEEQDEWYQALLELQRPAR 106

Phosphotyrosine-binding domain (IRS1-like);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189   162 KEVWQVILKPKGLGQTKNlIGIYRLCLTNKTISFVK-LNSDAAAVVLQLLNIRRCGHSENFFFIEVGRSAVTGPGEFWMQ 240
Cdd:smart00310   1 KQFWVTIRKTEGLERCPL-SGSYRLRLTSEELVLWRgLNPRVELVVWPLLSLRRYGRDKVFFFFEAGRRCVSGPGEFTFQ 79

                           90       100
                   ....*....|....*....|...
gi 686616189   241 vddSVVAQNMHETILEAMRAMSE 263
Cdd:smart00310  80 ---TVVAQEIFQLVLEAMQAQKN 99

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189   19 GYLRK-----PKSMHKRFFVLRaasesgPARLEYYENEKkwRHKSGAPKRSIPLESCFN--INKRADSKNKHLVALYTKD 91
Cdd:pfam00169   5 GWLLKkgggkKKSWKKRYFVLF------DGSLLYYKDDK--SGKSKEPKGSISLSGCEVveVVASDSPKRKFCFELRTGE 76

                          90       100
                  ....*....|....*....|....
gi 686616189   92 EH----FAIAADSEPEQESWYQAL 111
Cdd:pfam00169  77 RTgkrtYLLQAESEEERKDWIKAI 100

Insulin receptor substrate (IRS) pleckstrin homology (PH) domain; Insulin receptor substrate (IRS) molecules are mediators in insulin signaling and play a role in maintaining basic cellular functions such as growth and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. IRS molecules have an N-terminal PH domain, followed by an IRS-like PTB domain which has a PH-like fold. 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.cytoskeletal associated molecules, and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189  13 SDVRKVGYLRKPKSMHKRFFVLRAASESGPARLEYYENEKKWRHKsGAPKRSIPLESCFNINKRADSKNKHLVALYTKDE 92
Cdd:cd01257    1 TDVRKSGYLKKLKTMRKRYFVLRAESHGGPARLEYYENEKKFRRN-AEPKRVIPLSSCFNINKRADAKHKHLIALYTKDE 79

                         90       100
                 ....*....|....*....|....*..
gi 686616189  93 HFAIAADSEPEQESWYQALLQLHNRAK 119
Cdd:cd01257   80 CFGLVAESEEEQDEWYQALLELQRPAR 106

Phosphotyrosine-binding domain (IRS1-like);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189   162 KEVWQVILKPKGLGQTKNlIGIYRLCLTNKTISFVK-LNSDAAAVVLQLLNIRRCGHSENFFFIEVGRSAVTGPGEFWMQ 240
Cdd:smart00310   1 KQFWVTIRKTEGLERCPL-SGSYRLRLTSEELVLWRgLNPRVELVVWPLLSLRRYGRDKVFFFFEAGRRCVSGPGEFTFQ 79

                           90       100
                   ....*....|....*....|...
gi 686616189   241 vddSVVAQNMHETILEAMRAMSE 263
Cdd:smart00310  80 ---TVVAQEIFQLVLEAMQAQKN 99

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 686616189    15 VRKVGYLRKP-----KSMHKRFFVLRaasesgPARLEYYENEKKwrHKSGAPKRSIPLESCfNINKRADS---KNKHLVA 86
Cdd:smart00233   1 VIKEGWLYKKsgggkKSWKKRYFVLF------NSTLLYYKSKKD--KKSYKPKGSIDLSGC-TVREAPDPdssKKPHCFE 71

                           90       100       110
                   ....*....|....*....|....*....|.
gi 686616189    87 LYTKDEH-FAIAADSEPEQESWYQALLQLHN 116
Cdd:smart00233  72 IKTSDRKtLLLQAESEEEREKWVEALRKAIA 102

Pleckstrin homology (PH) domain of Downstream of tyrosine kinase 4, 5, and 6 proteins; The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs. The C-terminal part of Dok contains multiple tyrosine phosphorylation sites that serve as potential docking sites for Src homology 2-containing proteins such as ras GTPase-activating protein and Nck, leading to inhibition of ras signaling pathway activation and the c-Jun N-terminal kinase (JNK) and c-Jun activation, respectively. There are 7 mammalian Dok members: Dok-1 to Dok-7. Dok-1 and Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment of p120 rasGAP by Dok-1 and Dok-2 is critical to their negative regulation. Dok-3 is a negative regulator of the activation of JNK and mobilization of Ca2+ in B-cell receptor-mediated signaling, interacting with SHIP-1 and Grb2. Dok-4- 6 play roles in protein tyrosine kinase(PTK)-mediated signaling in neural cells and Dok-7 is the key cytoplasmic activator of MuSK (Muscle-Specific Protein Tyrosine Kinase). In general, PH domains have diverse functions, but are generally 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. 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 686616189  17 KVGYL----RKPKSMHKRFFVLRAASESGPARLEYYENEKKWRHKSGapKRSIPLESCFNINKRADSKNKHLVALYTKDE 92
Cdd:cd14678    2 KQGYVrirsRKLGIYRRCWLVFRKASSKGPKRLEKYPDERAAYLRAC--HKVTELSNVKNITRLPKETKRHAVAIIFTDD 79

                         90       100
                 ....*....|....*....|..
gi 686616189  93 HF-AIAADSEPEQESWYQALLQ 113
Cdd:cd14678   80 SSkTFACDSELEAEEWCKVLSM 101

Dedicator of cytokinesis-D subfamily Pleckstrin homology (PH) domain; DOCK-D subfamily (also called Zizimin subfamily) consists of Dock9/Zizimin1, Dock10/Zizimin3, and Dock11/Zizimin2. DOCK-D has a N-terminal DUF3398 domain, a PH-like domain, a Dock Homology Region 1, DHR1 (also called CZH1), a C2 domain, and a C-terminal DHR2 domain (also called CZH2). Zizimin1 is enriched in the brain, lung, and kidney; zizimin2 is found in B and T lymphocytes, and zizimin3 is enriched in brain, lung, spleen and thymus. Zizimin1 functions in autoinhibition and membrane targeting. Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration. No function has been determined for Zizimin3 to date. The N-terminal half of zizimin1 binds to the GEF domain through three distinct areas, including CZH1, to inhibit the interaction with Cdc42. In addition its PH domain binds phosphoinositides and mediates zizimin1 membrane targeting. DOCK is a family of proteins involved in intracellular signalling networks. They act as guanine nucleotide exchange factors for small G proteins of the Rho family, such as Rac and Cdc42. There are 4 subfamilies of DOCK family proteins based on their sequence homology: A-D. 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 686616189  13 SDVRKVGYLRK-------------PKSMHKRFFVLRAASEsGPARLEYYENEKKwrhksGAPKRSIPLESCFNI--NKRa 77
Cdd:cd13267    4 SGITKEGYLYKgpenssdsfislaMKSFKRRFFHLKQLVD-GSYILEFYKDEKK-----KEAKGTIFLDSCTGVvqNSK- 76

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 686616189  78 dsKNKHLVALYTKD-EHFAIAADSEPEQESWYQAL 111
Cdd:cd13267   77 --RRKFCFELRMQDkKSYVLAAESEAEMDEWISKL 109

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 686616189 172 KGLGQTKNLIGIYRLCLTNKTISFVKLNSDAAAVVLQLLNIRRCGH---SENFFFIEVGRSAVTGPGEFWMQVDDSVVAQ 248
Cdd:cd00934   31 AALKSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRdpdNPNVFAFIAGEEGGSGFRCHVFQCEDEEEAE 110

                         90
                 ....*....|
gi 686616189 249 NMHETILEAM 258
Cdd:cd00934  111 EILQAIGQAF 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 686616189  14 DVRKVGYLRK--PKSMHKRF------FVLRAASESG-PARLEYYENEKkwrhkSGAPKRSIPLESC------FNINKRaD 78
Cdd:cd01266    3 EVVCSGWLRKspPEKKLRRYawkkrwFVLRSGRLSGdPDVLEYYKNDH-----AKKPIRVIDLNLCeqvdagLTFNKK-E 76

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 686616189  79 SKNKHLVALYTKDEHFAIAADSEPEQESWYQALLQL 114
Cdd:cd01266   77 LENSYIFDIKTIDRIFYLVAETEEDMNKWVRNICDI 112

Myosin X Pleckstrin homology (PH) domain, repeat 2; 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 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 686616189  17 KVGYLRKP---------KSMHKRFFVLRAAsesgpaRLEYYENEkkwrHKSGAPKRSIPLESCFNINKRADSKNKhlVAL 87
Cdd:cd13296    1 KSGWLTKKgggsstlsrRNWKSRWFVLRDT------VLKYYEND----QEGEKLLGTIDIRSAKEIVDNDPKENR--LSI 68

                         90       100       110
                 ....*....|....*....|....*....|.
gi 686616189  88 YTKDEHFAIAADSEPEQESWYQALLQLHNRA 118
Cdd:cd13296   69 TTEERTYHLVAESPEDASQWVNVLTRVISAT 99

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 686616189  17 KVGYLRK------PKSMHKRFFVLRAASesgparLEYYENEKkwrhkSGAPKRSIPLESCFNINKRADSKnkhlVALYTK 90
Cdd:cd13253    2 KSGYLDKqggqgnNKGFQKRWVVFDGLS------LRYFDSEK-----DAYSKRIIPLSAISTVRAVGDNK----FELVTT 66

                         90       100
                 ....*....|....*....|...
gi 686616189  91 DEHFAIAADSEPEQESWYQALLQ 113
Cdd:cd13253   67 NRTFVFRAESDDERNLWCSTLQA 89

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 686616189  14 DVRKVGYLRKP-----KSMHKRFFVLRAAsesgpaRLEYYENEKKwrhksGAPKRSIPLEScFNI---NKRADSKNKHlv 85
Cdd:cd13248    6 PVVMSGWLHKQggsglKNWRKRWFVLKDN------CLYYYKDPEE-----EKALGSILLPS-YTIspaPPSDEISRKF-- 71

                         90       100       110
                 ....*....|....*....|....*....|...
gi 686616189  86 alYTKDEHFA-----IAADSEPEQESWYQALLQ 113
Cdd:cd13248   72 --AFKAEHANmrtyyFAADTAEEMEQWMNAMSL 102

Grb2-associated binding protein family 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. Members here include insect, nematodes, and crustacean Gab2s. 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 686616189  29 KRFFVLRAASESGPARLEYYENEKKWRHKSgapkrSIPLESCFNINK--RADSKNK----HLVALYTKDEHFAIAADSEP 102
Cdd:cd13384   25 RRYFVLRQSEIPGQYFLEYYTDRTCRKLKG-----SIDLDQCEQVDAglTFETKNKlkdqHIFDIRTPKRTYYLVADTED 99

                         90
                 ....*....|.
gi 686616189 103 EQESWYQALLQ 113
Cdd:cd13384  100 EMNKWVNCICT 110