Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. 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 24643405  489 DSHNQLQMDGPLYMKADPKKGWKRYHFVLRSSGLYYFPKEKTKNTRDLACLNLFHGHNVYTGLGWRKKWKSPTDYTFGFK 568
Cdd:cd01259    1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLK 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 24643405  569 AVgdSSLGKSCRSLKMLCAEDLPTLDRWLTAIRVCKYGKQLWDSHK 614
Cdd:cd01259   81 PN--KQQEKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. 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 24643405  489 DSHNQLQMDGPLYMKADPKKGWKRYHFVLRSSGLYYFPKEKTKNTRDLACLNLFHGHNVYTGLGWRKKWKSPTDYTFGFK 568
Cdd:cd01259    1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLK 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 24643405  569 AVgdSSLGKSCRSLKMLCAEDLPTLDRWLTAIRVCKYGKQLWDSHK 614
Cdd:cd01259   81 PN--KQQEKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405    367 RLFVKAFTSDGAS----KSLLVDERMGCGHVTRLLADKNHV-QMQSNWALVEHLGDLQMERLFEDHELLVDNLMTWHSDA 441
Cdd:pfam00788    2 DGVLKVYTEDGKPgttyKTILVSSSTTAEEVIEALLEKFGLeDDPRDYVLVEVLERGGGERRLPDDECPLQIQLQWPRDA 81

                           90
                   ....*....|..
gi 24643405    442 GN-RVLFQQRPD 452
Cdd:pfam00788   82 SDsRFLLRKRDD 93

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Kalhammer et al. have shown that not all RA domains bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase. Predicted RA domains in PLC210 and nore1 found to bind RasGTP. Included outliers (Grb7, Grb14, adenylyl cyclases etc.)

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405     372 AFTSDGASKSLLVDERMGCGHVTRLLADKNHVQMQSN-WALVEHLGDlQMERLFEDHELLVDNLMTWHSDAGN-RVLFQQ 449
Cdd:smart00314   10 DDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEeYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRGPNlRFVLRK 88

                    ..
gi 24643405     450 RP 451
Cdd:smart00314   89 RD 90

Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. 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 24643405  489 DSHNQLQMDGPLYMKADPKKGWKRYHFVLRSSGLYYFPKEKTKNTRDLACLNLFHGHNVYTGLGWRKKWKSPTDYTFGFK 568
Cdd:cd01259    1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLK 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 24643405  569 AVgdSSLGKSCRSLKMLCAEDLPTLDRWLTAIRVCKYGKQLWDSHK 614
Cdd:cd01259   81 PN--KQQEKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

Ras-associating (RA) domain of Mig10/RIAM/Lpd (MRL) family; MRL proteins share a common structural architecture, including a central structural unit consisting of a Ras-associating (RA) domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RA and PH form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain. MRL proteins have distinct functions in cell migration and adhesion, signaling, and in cell growth.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405  367 RLFVKAFTSDGASKSLLVDERMGCGHVTRLLADKNHVQMQSNWALVEHLGDLQMERLFEDHELLVDNLMTWHSDAGNRVL 446
Cdd:cd01787    1 KLVVKVHMEDGSSKTLLVDERMTVRQVLKQLIEKNHCDPSVDWCLVEQYPDLYMERVFEDHEKLVENLLNWTRDSTNKLL 80

                 ....*
gi 24643405  447 FQQRP 451
Cdd:cd01787   81 FLERT 85

Ras-associating (RA) domain found in the adapter protein lamellipodin (Lpd); Lpd, also termed Ras-associated and pleckstrin homology domains-containing protein 1 (RAPH1), or amyotrophic lateral sclerosis 2 chromosomal region candidate gene 18 protein, or amyotrophic lateral sclerosis 2 chromosomal region candidate gene 9 protein, or proline-rich EVH1 ligand 2 (PREL-2), or protein RMO1, is a member of MRL (Mig10/RIAM/Lpd) family proteins that regulates cell migration and promote lamellipodia protrusion in fibroblast by interacting with Ena/VASP proteins. MRL proteins share a common structural architecture, including a central structural unit consisting of an RA domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. Lpd also contains a helical region at the amino terminus for talin binding. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RA and PH domain in Lpd form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain. Lpd also exhibits other unique enzymatic functions including its catalytic activity of butyrylcholinesterase, a potent therapeutic treatment targeting cocaine abuse.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405  365 IRRLFVKAFTSDGASKSLLVDERMGCGHVTRLLADKNHVQMQSNWALVEHLGDLQMERLFEDHELLVDNLMTWHSDAGNR 444
Cdd:cd16136    2 VKKLVIRVHMSDDSSKTMMVDERQTVRQVLDNLMDKSHCGYSLDWSLVETISELQMERIFEDHENLVENLLNWTRDSQNK 81

                 ....*....
gi 24643405  445 VLFQQRPDK 453
Cdd:cd16136   82 LMFVERIEK 90

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405    367 RLFVKAFTSDGAS----KSLLVDERMGCGHVTRLLADKNHV-QMQSNWALVEHLGDLQMERLFEDHELLVDNLMTWHSDA 441
Cdd:pfam00788    2 DGVLKVYTEDGKPgttyKTILVSSSTTAEEVIEALLEKFGLeDDPRDYVLVEVLERGGGERRLPDDECPLQIQLQWPRDA 81

                           90
                   ....*....|..
gi 24643405    442 GN-RVLFQQRPD 452
Cdd:pfam00788   82 SDsRFLLRKRDD 93

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 7; GRB7, also termed B47, or epidermal growth factor receptor GRB-7, or GRB7 adapter protein, is a signal-transducing cytoplasmic adaptor protein that is co-opted by numerous tyrosine kinases involved in various cellular signaling and functions. Grb7 and its related family members Grb10 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm. Grb7 could interact with activated N-Ras in transfected cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405  370 VKAFTSDGASKSLLVDERMGCGHVTRLLADKNHVQMQSNWALVEHLGDLQMERLFEDHELLVDNLMTWHSDAGNRVLFQQ 449
Cdd:cd16140    5 VKVYSEDGTCRSLEVTAGATARHVCEMLVQRAHCLDDESWSLVELHPHLALERCLEDHESVVEVQATWPAGGDSRFVFRK 84

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, also termed insulin receptor-binding protein Grb-IR, is a multi-domain cytoplasmic adaptor protein that binds to the insulin-like growth factor 1 receptor (IGF-1R) and inhibits insulin signaling. Grb10 and its related family members Grb7 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm. Grb14 binds to both GTPase-defective mutant Rab5 as well as CNGA1, whereas Grb10 binds only to GTP-bound form of active Rab5.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405  370 VKAFTSDGASKSLLVDERMGCGHVTRLLADKNHVQMQSNWALVEHLGDLQMERLFEDHELLVDNLMTWHSDAgnRVLFQQ 449
Cdd:cd16141    5 VKVFSEDGTSKVVEILADMTARDLCQLLVYKSHCVDDNSWTLVEHHPHLGLERCLEDHELVVQVQSTMGSES--KFLFRK 82

                 ....*...
gi 24643405  450 RPDKVTLF 457
Cdd:cd16141   83 NYAKYEFF 90

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Kalhammer et al. have shown that not all RA domains bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase. Predicted RA domains in PLC210 and nore1 found to bind RasGTP. Included outliers (Grb7, Grb14, adenylyl cyclases etc.)

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24643405     372 AFTSDGASKSLLVDERMGCGHVTRLLADKNHVQMQSN-WALVEHLGDlQMERLFEDHELLVDNLMTWHSDAGN-RVLFQQ 449
Cdd:smart00314   10 DDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPEeYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRGPNlRFVLRK 88

                    ..
gi 24643405     450 RP 451
Cdd:smart00314   89 RD 90

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 24643405  496 MDGPLYMK-ADPKKGWKRYHFVLRSSGLYYFPKEKTKNTRDLACLNLFHGHNVytglgwrkKWKSPTDYTFGFKAVGDSS 574
Cdd:cd00821    1 KEGYLLKRgGGGLKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGILEV--------EEVSPKERPHCFELVTPDG 72

                         90       100
                 ....*....|....*....|....*.
gi 24643405  575 lgkscRSLKmLCAEDLPTLDRWLTAI 600
Cdd:cd00821   73 -----RTYY-LQADSEEERQEWLKAL 92

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in Dictyostelium discoideum Myosin-VIIa (DdMyo7) and similar proteins; DdMyo7, also termed Myosin-I heavy chain, or class VII unconventional myosin, or M7, plays a role in adhesion in Dictyostelium where it is a component of a complex of proteins that serve to link membrane receptors to the underlying actin cytoskeleton. It interacts with talinA, an actin-binding protein with a known role in cell-substrate adhesion. DdMyo7 is required for phagocytosis. It is also essential for the extension of filopodia, plasma membrane protrusions filled with parallel bundles of F-actin. Members in this family contain a myosin motor domain, two MyTH4 domains, two FERM (Band 4.1, ezrin, radixin, moesin) domains, and two Pleckstrin homology (PH) domains. Some family members contain an extra SH3 domain. Each FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 24643405  366 RRLFVKAFTSDGASKSLLVDERMGCGHVTRLLADKnhVQMQSN---WALVEHLGDLqmERLFEDHELLVDNLMTW 437
Cdd:cd17208    2 RPIVARFYFLDGQFKALEFDSAATAAEVLEQLKQK--IGLRSTadgFALYEVFGGI--ERAILPEEKVADVLSKW 72