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 568913999 243 SIIVPELEGALYLKEDGKKSWKRRYFLLRASGIYYVPKGKTKTSRDLACFIQFENVNIYYGIQCKMKYKAPTDHCFVLKH 322
Cdd:cd01259    2 SVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLKP 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 568913999 323 PQIQ-KESQYIKYLCCDDARTLSQWVMGIRIAKYGKTLYDNYQ 364
Cdd:cd01259   82 NKQQeKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 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 568913999 243 SIIVPELEGALYLKEDGKKSWKRRYFLLRASGIYYVPKGKTKTSRDLACFIQFENVNIYYGIQCKMKYKAPTDHCFVLKH 322
Cdd:cd01259    2 SVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLKP 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 568913999 323 PQIQ-KESQYIKYLCCDDARTLSQWVMGIRIAKYGKTLYDNYQ 364
Cdd:cd01259   82 NKQQeKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568913999   121 DDSSTKSLMVDERQLARDVLDNLFEKTHCDCNV-DWCLYEIYPElQIERVFEDHENVVEVLSDWTRDTENKVLFLEKEE 198
Cdd:smart00314  13 PGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPeEYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRGPNLRFVLRKRD 90

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568913999  247 PELEGALYLKEDG-KKSWKRRYFLLRASGIYYVPKGKTKTSRDLACFIQFENVNIYYGIQCKMKykaPTDHCFVLKHPQI 325
Cdd:pfam00169   1 VVKEGWLLKKGGGkKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVVASDSP---KRKFCFELRTGER 77

                          90       100       110
                  ....*....|....*....|....*....|
gi 568913999  326 QKESQYikYLCCDDARTLSQWVMGIRIAKY 355
Cdd:pfam00169  78 TGKRTY--LLQAESEEERKDWIKAIQSAIR 105

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 568913999 243 SIIVPELEGALYLKEDGKKSWKRRYFLLRASGIYYVPKGKTKTSRDLACFIQFENVNIYYGIQCKMKYKAPTDHCFVLKH 322
Cdd:cd01259    2 SVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLKP 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 568913999 323 PQIQ-KESQYIKYLCCDDARTLSQWVMGIRIAKYGKTLYDNYQ 364
Cdd:cd01259   82 NKQQeKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568913999 119 HMDDSSTKSLMVDERQLARDVLDNLFEKTHCDCNVDWCLYEIYPELQIERVFEDHENVVEVLSDWTRDTENKVLFLEKE 197
Cdd:cd01787    7 HMEDGSSKTLLVDERMTVRQVLKQLIEKNHCDPSVDWCLVEQYPDLYMERVFEDHEKLVENLLNWTRDSTNKLLFLERT 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 568913999 119 HMDDSSTKSLMVDERQLARDVLDNLFEKTHCDCNVDWCLYEIYPELQIERVFEDHENVVEVLSDWTRDTENKVLFLEKEE 198
Cdd:cd16136   10 HMSDDSSKTMMVDERQTVRQVLDNLMDKSHCGYSLDWSLVETISELQMERIFEDHENLVENLLNWTRDSQNKLMFVERIE 89

                 .
gi 568913999 199 R 199
Cdd:cd16136   90 K 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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 568913999   121 DDSSTKSLMVDERQLARDVLDNLFEKTHCDCNV-DWCLYEIYPElQIERVFEDHENVVEVLSDWTRDTENKVLFLEKEE 198
Cdd:smart00314  13 PGGTYKTLRVSSRTTARDVIQQLLEKFHLTDDPeEYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRGPNLRFVLRKRD 90

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568913999 121 DDSSTKSLMVDERQLARDVLDNLFEKTHCDCNVDWCLYEIYPELQIERVFEDHENVVEVLSDWTRDTENKVLF 193
Cdd:cd16140   10 EDGTCRSLEVTAGATARHVCEMLVQRAHCLDDESWSLVELHPHLALERCLEDHESVVEVQATWPAGGDSRFVF 82

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568913999  247 PELEGALYLKEDG-KKSWKRRYFLLRASGIYYVPKGKTKTSRDLACFIQFENVNIYYGIQCKMKykaPTDHCFVLKHPQI 325
Cdd:pfam00169   1 VVKEGWLLKKGGGkKKSWKKRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVVASDSP---KRKFCFELRTGER 77

                          90       100       110
                  ....*....|....*....|....*....|
gi 568913999  326 QKESQYikYLCCDDARTLSQWVMGIRIAKY 355
Cdd:pfam00169  78 TGKRTY--LLQAESEEERKDWIKAIQSAIR 105

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 14; Grb14, a member of cytoplasmic adaptor proteins, is a tissue-specific negative regulator of insulin signaling. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ubi is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. A novel function of Grb14 RA domain is to interact with the nucleotide binding pocket of a cyclic nucleotide gated channel alpha subunit (CNGA1) and inhibits its activity. 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 PH domains, and a carboxyl-terminal SH2 domain. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568913999 121 DDSSTKSLMVDERQLARDVLDNLFEKTHCDCNVDWCLYEIYPELQIERVFEDHENVVEVLSDWTRDTENKVLF 193
Cdd:cd16139    9 EDDTSRALEVPNDITARDVCQLFILKNHYIDDHSWTLFEHLPHIGLERIIEDHESVIEVQSNWGMETDSRLYF 81

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 568913999 121 DDSSTKSLMVDERQLARDVLDNLFEKTHCDCNVDWCLYEIYPELQIERVFEDHENVVEVLSDWTrdTENKVLFLEKEERY 200
Cdd:cd16141   10 EDGTSKVVEILADMTARDLCQLLVYKSHCVDDNSWTLVEHHPHLGLERCLEDHELVVQVQSTMG--SESKFLFRKNYAKY 87

                 ....*
gi 568913999 201 AVFKN 205
Cdd:cd16141   88 EFFKN 92

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 568913999 249 LEGALYLKEDG-KKSWKRRYFLLRASGIYYVpKGKTKTSRDLACFIQFENVniyygIQCKMKYKAPTDHCFVLKHPqiqK 327
Cdd:cd00821    1 KEGYLLKRGGGgLKSWKKRWFVLFEGVLLYY-KSKKDSSYKPKGSIPLSGI-----LEVEEVSPKERPHCFELVTP---D 71

                         90       100
                 ....*....|....*....|
gi 568913999 328 ESQYikYLCCDDARTLSQWV 347
Cdd:cd00821   72 GRTY--YLQADSEEERQEWL 89

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 5; 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 five 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 568913999 250 EGALYLKEDGKK-----SWKRRYFLLRASGIY-YVPKGKTKTSRDlacfIQFENVNIYYGIqcKMKYKAPTDHCFVLKHP 323
Cdd:cd13259   16 HGMLKFREEPSKllsgnKFQDRYFILNDECLLlYKDVKSSKPEKE----WPLKSLKVYLGI--KKKLKPPTSWGFTVLLE 89

                         90       100       110
                 ....*....|....*....|....*....|...
gi 568913999 324 QIQKesqyikYLCCDDARTLSQWVMGIRIAKYG 356
Cdd:cd13259   90 KQQW------YLCCDSQMEQREWMATILSAQHD 116

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 568913999 247 PELEGALYLKEDGK----KSWKRRYFLLRASGIY-YVPKGKTKTSRdlacFIQFENVNIYYGIQCKMKYkaptdhCFVLK 321
Cdd:cd01260   13 GDCQGWLWKKKEAKsffgQKWKKYWFVLKGSSLYwYSNQQDEKAEG----FINLPDFKIERASECKKKY------AFKAC 82

                         90       100
                 ....*....|....*....|....*.
gi 568913999 322 HPQIQKesqyiKYLCCDDARTLSQWV 347
Cdd:cd01260   83 HPKIKT-----FYFAAENLDDMNKWL 103