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 2809059    31 VRKCGYLRKQKHGHKRFFVLRGPGAGGdkatagggsapqPPRLEYYESEKNWRSKAgAPKRVIALDCCLNINKRADPKHK 110
Cdd:cd01257    3 VRKSGYLKKLKTMRKRYFVLRAESHGG------------PARLEYYENEKKFRRNA-EPKRVIPLSSCFNINKRADAKHK 69

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 2809059   111 YLIALYTKDEYFAVAAENEQEQEGWYRALTDLVSEGR 147
Cdd:cd01257   70 HLIALYTKDECFGLVAESEEEQDEWYQALLELQRPAR 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 2809059    31 VRKCGYLRKQKHGHKRFFVLRGPGAGGdkatagggsapqPPRLEYYESEKNWRSKAgAPKRVIALDCCLNINKRADPKHK 110
Cdd:cd01257    3 VRKSGYLKKLKTMRKRYFVLRAESHGG------------PARLEYYENEKKFRRNA-EPKRVIPLSSCFNINKRADAKHK 69

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 2809059   111 YLIALYTKDEYFAVAAENEQEQEGWYRALTDLVSEGR 147
Cdd:cd01257   70 HLIALYTKDECFGLVAESEEEQDEWYQALLELQRPAR 106

Phosphotyrosine-binding domain (IRS1-like);

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2809059      196 EVWQVNLKPKGLGQSKNlTGVYRLCLSARTIGFVK-LNCEQPSVTLQLMNIRRCGHSDSFFFIEVGRSAVTGPGELWMQa 274
Cdd:smart00310    2 QFWVTIRKTEGLERCPL-SGSYRLRLTSEELVLWRgLNPRVELVVWPLLSLRRYGRDKVFFFFEAGRRCVSGPGEFTFQ- 79

                            90       100
                    ....*....|....*....|..
gi 2809059      275 ddSVVAQNIHETILEAMKALKE 296
Cdd:smart00310   80 --TVVAQEIFQLVLEAMQAQKN 99

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2809059      31 VRKCGYLRKQKHG-----HKRFFVLRGPgaggdkatagggsapqppRLEYYESEKnwRSKAGAPKRVIALDCC--LNINK 103
Cdd:pfam00169    1 VVKEGWLLKKGGGkkkswKKRYFVLFDG------------------SLLYYKDDK--SGKSKEPKGSISLSGCevVEVVA 60

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 2809059     104 RADPKHKYLIALYT-----KDEYFaVAAENEQEQEGWYRALTDLVS 144
Cdd:pfam00169   61 SDSPKRKFCFELRTgertgKRTYL-LQAESEEERKDWIKAIQSAIR 105

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 2809059    31 VRKCGYLRKQKHGHKRFFVLRGPGAGGdkatagggsapqPPRLEYYESEKNWRSKAgAPKRVIALDCCLNINKRADPKHK 110
Cdd:cd01257    3 VRKSGYLKKLKTMRKRYFVLRAESHGG------------PARLEYYENEKKFRRNA-EPKRVIPLSSCFNINKRADAKHK 69

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 2809059   111 YLIALYTKDEYFAVAAENEQEQEGWYRALTDLVSEGR 147
Cdd:cd01257   70 HLIALYTKDECFGLVAESEEEQDEWYQALLELQRPAR 106

Phosphotyrosine-binding domain (IRS1-like);

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2809059      196 EVWQVNLKPKGLGQSKNlTGVYRLCLSARTIGFVK-LNCEQPSVTLQLMNIRRCGHSDSFFFIEVGRSAVTGPGELWMQa 274
Cdd:smart00310    2 QFWVTIRKTEGLERCPL-SGSYRLRLTSEELVLWRgLNPRVELVVWPLLSLRRYGRDKVFFFFEAGRRCVSGPGEFTFQ- 79

                            90       100
                    ....*....|....*....|..
gi 2809059      275 ddSVVAQNIHETILEAMKALKE 296
Cdd:smart00310   80 --TVVAQEIFQLVLEAMQAQKN 99

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2809059    33 KCGYLRKQ-----KHGHKRFFVLRGPgaggdkatagggsapqppRLEYYESEKNWRSKagaPKRVIALDCCLNINKRADP 107
Cdd:cd00821    1 KEGYLLKRgggglKSWKKRWFVLFEG------------------VLLYYKSKKDSSYK---PKGSIPLSGILEVEEVSPK 59

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 2809059   108 KHKYLIALYTKDE---YFAvaAENEQEQEGWYRAL 139
Cdd:cd00821   60 ERPHCFELVTPDGrtyYLQ--ADSEEERQEWLKAL 92

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 2809059   205 KGLGQSKNLTGVYRLCLSARTIGFVKLNCEQPSVTLQLMNIRRCGHSDS----FFFIeVGRSAVTGPGELWMQADDSVVA 280
Cdd:cd00934   31 AALKSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHRISYCGRDPDnpnvFAFI-AGEEGGSGFRCHVFQCEDEEEA 109

                         90
                 ....*....|.
gi 2809059   281 QNIHETILEAM 291
Cdd:cd00934  110 EEILQAIGQAF 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 2809059    45 KRFFVLRGPGAGGDkatagggsapqPPRLEYYeseKNWRSKAgaPKRVIALDCC------LNINKRaDPKHKYLIALYTK 118
Cdd:cd01266   26 KRWFVLRSGRLSGD-----------PDVLEYY---KNDHAKK--PIRVIDLNLCeqvdagLTFNKK-ELENSYIFDIKTI 88

                         90       100
                 ....*....|....*....|....
gi 2809059   119 DEYFAVAAENEQEQEGWYRALTDL 142
Cdd:cd01266   89 DRIFYLVAETEEDMNKWVRNICDI 112

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 2809059    45 KRFFVLRgpgAGGDKATAgggsapqpprLEYYESEKnwrskAGAPKRVIALDCCLNI--NKRadpKHKYLIALYTKD-EY 121
Cdd:cd13267   33 RRFFHLK---QLVDGSYI----------LEFYKDEK-----KKEAKGTIFLDSCTGVvqNSK---RRKFCFELRMQDkKS 91

                         90
                 ....*....|....*...
gi 2809059   122 FAVAAENEQEQEGWYRAL 139
Cdd:cd13267   92 YVLAAESEAEMDEWISKL 109

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 2809059    30 SVRKCGYLRKQ----KHGHKRFFVLRgpgaggdkatagggsapqPPRLEYYESEKNWRSKAGAPKRVIalDCCLNINKRa 105
Cdd:cd13255    5 AVLKAGYLEKKgerrKTWKKRWFVLR------------------PTKLAYYKNDKEYRLLRLIDLTDI--HTCTEVQLK- 63

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 2809059   106 dpKHKYLIALYTKDEYFAVAAENEQEQEGWYRALTD 141
Cdd:cd13255   64 --KHDNTFGIVTPARTFYVQADSKAEMESWISAINL 97