DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. 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 2024334814  827 AITGYDGNLNELGKLLMQGSFNVWTDHKKGHSKvkDLARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKHSLN 906
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2024334814  907 MAAVGITENVKGDAKKFEIWYNAREEVYIIQAPTPEVKATWVNEIRKVLTSQ 958
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Src homology 3 domain of DBL's Big Sister (DBS), a guanine nucleotide exchange factor; DBS, also called MCF2L (MCF2-transforming sequence-like protein) or OST, is a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42. Depending on cell type, DBS can also activate RhoA and RhoG. DBS contains a Sec14-like domain, spectrin-like repeats, a RhoGEF [or Dbl homology (DH)] domain, a Pleckstrin homology (PH) domain, and an SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKNLTTGREGWIPANNLLM 1127
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQWLVKNLSTRKEGWVPAANLQP 55

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  367 FEQNFREVKAALDIVSERLSAF--TDVGNSCSHVEHILKDLANFEEKSCETVAKARMLASEGDAFIQSNHYAVDSIIPKC 444
Cdd:cd00176      2 LQQFLRDADELEAWLSEKEELLssTDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQERL 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  445 SELHHLCDAFTTEMEQRRNVLNKSLELHGLLEKS---MKWCDEGIYLLASQPVDKcqSQDGAESALQEIEKFLDT--GAG 519
Cdd:cd00176     82 EELNQRWEELRELAEERRQRLEEALDLQQFFRDAddlEQWLEEKEAALASEDLGK--DLESVEELLKKHKELEEEleAHE 159

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|
gi 2024334814  520 NKIKELNKVYREYAHILNEDLKEHIQKVF----QKQESMEEMFQKRQVSL 565
Cdd:cd00176    160 PRLKSLNELAEELLEEGHPDADEEIEEKLeelnERWEELLELAEERQKKL 209

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. 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 2024334814  827 AITGYDGNLNELGKLLMQGSFNVWTDHKKGHSKvkDLARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKHSLN 906
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2024334814  907 MAAVGITENVKGDAKKFEIWYNAREEVYIIQAPTPEVKATWVNEIRKVLTSQ 958
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   646 VMNELIETERAYVEELLCVLEGYAAEMDNPLMAhlispELQNKKDILFGNMEEIYHFHnRIFLRELENYVEY----PELV 721
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFH-RDFLDELEERIEEwddsVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   722 GRCFLDQMEDFQIYEKYCQNKPRSESLWRQFSDSIFFQECQRKLDHK-----LSLDSYLLKPVQRITKYQLLLKEMLKYS 796
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSpqcrrLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 2024334814   797 K-NCEGAEDLQEALNSILGILKAVND 821
Cdd:smart00325  155 PeDHEDREDLKKALKAIKELANQVNE 180

Src homology 3 domain of DBL's Big Sister (DBS), a guanine nucleotide exchange factor; DBS, also called MCF2L (MCF2-transforming sequence-like protein) or OST, is a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42. Depending on cell type, DBS can also activate RhoA and RhoG. DBS contains a Sec14-like domain, spectrin-like repeats, a RhoGEF [or Dbl homology (DH)] domain, a Pleckstrin homology (PH) domain, and an SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKNLTTGREGWIPANNLLM 1127
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQWLVKNLSTRKEGWVPAANLQP 55

Divergent CRAL/TRIO domain; This family includes divergent members of the CRAL-TRIO domain family. This family includes ECM25 that contains a divergent CRAL-TRIO domain identified by Gallego and colleagues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  102 GCPVITFPDYPAFSE-IPEKEFQNVLTYLTSIPSLRDAGIGFILVIDRRQDKWTS------VKASILRIAASFPGNLQLV 174
Cdd:pfam13716    1 GRPVLVFISKLLPSRpASLDDLDRLLFYLLKTLSEKLKGKPFVVVVDHTGVTSENfpslsfLKKAYDLLPRAFKKNLKAV 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2024334814  175 LVLRPTGLIHRALSDIAFKFNRDEFKMKVpiIMLGSVSELQGYIDKTQLTEDLGGTLDYCHN 236
Cdd:pfam13716   81 YVVHPSTFLRTFLKTLGSLLGSKKLRKKV--HYVSSLSELWEGIDREQLPTELPGVLSYDEE 140

Sec14p-like lipid-binding domain; Sec14p-like lipid-binding domains are found in secretory proteins, such as S. cerevisiae phosphatidylinositol transfer protein (Sec14p), and in lipid regulated proteins such as RhoGAPs, RhoGEFs and neurofibromin (NF1). SEC14 domain of Dbl is known to associate with G protein beta/gamma subunits.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   82 DIHDQLKKqfAYLSGGRGGDGCPVITF-PDYPAFSEIPEKEFQNVLTYL--TSIPSLRDAGIGFILVIDRRQDKWTS--- 155
Cdd:cd00170      3 ELLELLGG--IGYLGGRDKEGRPVLVFrAGWDPPKLLDLEELLRYLVYLleKALRELEEQVEGFVVIIDLKGFSLSNlsd 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024334814  156 ---VKASILRIAASFPGNLQLVLVLRPTGLIhRALSDIAFKFNRDEFKMKvpIIMLGS-VSELQGYIDKTQLTEDLGGT 230
Cdd:cd00170     81 lslLKKLLKILQDHYPERLKKIYIVNAPWIF-SALWKIVKPFLSEKTRKK--IVFLGSdLEELLEYIDPDQLPKELGGT 156

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  532 YAHILNEDLKEHIQkvFQKQESMEEMFQKRQVS-------LKKLAAKQTRPVQPVAPRPEAFVKSPCTspgLQRDCVSNT 604
Cdd:COG5422    344 YDHRLRDSRIEIYQ--LRGYSDMRIAHNFPTSStsfenmgKATLTNSSSSTNEPATPKAEYNPNGVFT---LLTECYSST 418

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  605 ESgvLRKVNY-----RRGKSEMSELHQSRGG----STM-----DDEENLAVL----------------RQHVMNELIETE 654
Cdd:COG5422    419 CS--RDELCYsiscpRRLEQQARLHLKLMGGlkrnSSLaldkfDEEKNLWTLsvpkevweslpkqeikRQEAIYEVIYTE 496

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  655 RAYVEELlcvlEGYAAEMDNPLMAHLISPELQNKKDI--LFGNMEEIYHFHNRIF--LRELENYVEYPELVGRCFLDQME 730
Cdd:COG5422    497 RDFVKDL----EYLRDTWIKPLEESNIIPENARRNFIkhVFANINEIYAVNSKLLkaLTNRQCLSPIVNGIADIFLDYVP 572

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  731 DFQIYEKYCQNKP-------RSESLWRQFSdsIFFQECQR-KLDHKLSLDSYLLKPVQRITKYQLLLKEMLKYSK-NCEG 801
Cdd:COG5422    573 KFEPFIKYGASQPyakyefeREKSVNPNFA--RFDHEVERlDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDpDNPD 650

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  802 AEDLQEALNSILGILKAVNdsmHQIAITGYDGNLNELGKLLM-------QGSFNVWTDHK-KGHSKVKDLARFKPMQR-- 871
Cdd:COG5422    651 TEDIPKVIDMLREFLSRLN---FESGKAENRGDLFHLNQQLLfkpeyvnLGLNDEYRKIIfKGVLKRKAKSKTDGSLRgd 727

                          410
                   ....*....|....*....
gi 2024334814  872 -HLFLHEKAVLFCKKREEN 889
Cdd:COG5422    728 iQFFLLDNMLLFCKAKAVN 746

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  853 HKKGHSKVKdlaRFKPmqRHLFLHEKAVLFCKKREengegyeKAPSYSYKHSLNMAAVGITENVKGDAKK----FEIWYN 928
Cdd:pfam00169    8 LKKGGGKKK---SWKK--RYFVLFDGSLLYYKDDK-------SGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRTG 75

                           90       100
                   ....*....|....*....|....*....
gi 2024334814  929 AR--EEVYIIQAPTPEVKATWVNEIRKVL 955
Cdd:pfam00169   76 ERtgKRTYLLQAESEEERKDWIKAIQSAI 104

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVknLTTGREGWIPANNL 1125
Cdd:pfam07653    1 YGRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEG--ETGGRVGLVPSTAV 51

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. 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 2024334814  827 AITGYDGNLNELGKLLMQGSFNVWTDHKKGHSKvkDLARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKHSLN 906
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2024334814  907 MAAVGITENVKGDAKKFEIWYNAREEVYIIQAPTPEVKATWVNEIRKVLTSQ 958
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   646 VMNELIETERAYVEELLCVLEGYAAEMDNPLMAhlispELQNKKDILFGNMEEIYHFHnRIFLRELENYVEY----PELV 721
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFH-RDFLDELEERIEEwddsVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   722 GRCFLDQMEDFQIYEKYCQNKPRSESLWRQFSDSIFFQECQRKLDHK-----LSLDSYLLKPVQRITKYQLLLKEMLKYS 796
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSpqcrrLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 2024334814   797 K-NCEGAEDLQEALNSILGILKAVND 821
Cdd:smart00325  155 PeDHEDREDLKKALKAIKELANQVNE 180

Puratrophin-1 pleckstrin homology (PH) domain; Puratrophin-1 (also called Purkinje cell atrophy-associated protein 1 or PLEKHG4/Pleckstrin homology domain-containing family G member 4) contains a spectrin repeat, a RhoGEF (DH) domain, and a PH domain. It is thought to function in intracellular signaling and cytoskeleton dynamics at the Golgi. Puratrophin-1 is expressed in kidney, Leydig cells in the testis, epithelial cells in the prostate gland and Langerhans islet in the pancreas. A single nucleotide substitution in the puratrophin-1 gene were once thought to result in autosomal dominant cerebellar ataxia (ADCA), but now it has been demonstrated that this ataxia is a result of defects in the BEAN gene. Puratrophin contains a domain architecture similar to that of Dbl family members Dbs and Trio. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a RhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 2024334814  820 NDSMHQIAITGYDGNLNELGKLLMQGSFNVWTDHKKGhskvkdlarfkpmQRHLFLHEKAVLFCKKReengegyeKAPS- 898
Cdd:cd13242      8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKPK--------KTPGg 66

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  899 ---YSYKHSLNMAAVGITENVKGDAKKFEIWYNARE--EVYIIQAPTPEVKATWVNEIRKVLTSqlQACR 963
Cdd:cd13242     67 kdvYIYKHSIKTSDIGLTENVGDSGLKFEIWFRRRKarDTYILQATSPEIKQAWTSDIAKLLWK--QAIR 134

Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p); Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) and in RhoGAPs, RhoGEFs and the RasGAP, neurofibromin (NF1). Lipid-binding domain. The SEC14 domain of Dbl is known to associate with G protein beta/gamma subunits.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814    87 LKKQFAYLSGGRGGD--GCPVITFPDY--PAFSEIPEKEFQNVLTYLTSIPSLRDAGI---GFILVIDRRQDKWTSVKAS 159
Cdd:smart00516    2 LELLKAYIPGGRGYDkdGRPVLIERAGrfDLKSVTLEELLRYLVYVLEKILQEEKKTGgieGFTVIFDLKGLSMSNPDLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2024334814   160 ILRIAAS-----FPGNLQLVLVLRPTGLIhRALSDIAFKFNRDEFKMKVPIIMLGSVSELQGYIDKTQLTEDLGGTLD 232
Cdd:smart00516   82 VLRKILKilqdhYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

Triple functional domain pleckstrin homology pleckstrin homology (PH) domain, repeat 1; RhoGEFs, Kalirin and Trio, the mammalian homologs of Drosophila Trio and Caenorhabditis elegans UNC-73 regulate a novel step in secretory granule maturation. Their signaling modulates the extent to which regulated cargo enter and remain in the regulated secretory pathway. This allows for fine tuning of peptides released by a single secretory cell type with impaired signaling leading to pathological states. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Kalirin and Trio are encoded by separate genes in mammals and by a single one in invertebrates. Kalirin and Trio share the same complex multidomain structure and display several splice variants. The longest Kalirin and Trio proteins have a Sec14 domain, a stretch of spectrin repeats, a RhoGEF(DH)/PH cassette (also called GEF1), an SH3 domain, a second RhoGEF(DH)/PH cassette (also called GEF2), a second SH3 domain, Ig/FNIII domains, and a kinase domain. The first RhoGEF(DH)/PH cassette catalyzes exchange on Rac1 and RhoG while the second RhoGEF(DH)/PH cassette is specific for RhoA. Kalirin and Trio are closely related to p63RhoGEF and have PH domains of similar function. 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  828 ITGYDGNLNELGKLLMQGSFNVWtDHKKGHSKVKDlarfkpmqRHLFLHEKAVLFCKKrEENGEGYEKapsYSYKHSLNM 907
Cdd:cd13240      2 LEGCDEDLDSLGEVILQDSFQVW-DPKQLIRKGRE--------RHVFLFELCLVFSKE-VKDSNGKSK---YIYKSRLMT 68

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2024334814  908 AAVGITENVKGDAKKFEIW---YNAREEVYIIQAPTPEVKATWVNEIRKVL 955
Cdd:cd13240     69 SEIGVTEHIEGDPCKFALWtgrVPTSDNKIVLKASSLEVKQTWVKKLREVI 119

Obscurin pleckstrin homology (PH) domain; Obscurin (also called Obscurin-RhoGEF; Obscurin-myosin light chain kinase/Obscurin-MLCK) is a giant muscle protein that is concentrated at the peripheries of Z-disks and M-lines. It binds small ankyrin I, a component of the sarcoplasmic reticulum (SR) membrane. It is associated with the contractile apparatus through binding with titin and sarcomeric myosin. It plays important roles in the organization and assembly of the myofibril and the SR. Obscurin has been observed as alternatively-spliced isoforms. The major isoform in sleletal muscle, approximately 800 kDa in size, is composed of many adhesion modules and signaling domains. It harbors 49 Ig and 2 FNIII repeats at the N-terminues, a complex middle region with additional Ig domains, an IQ motif, and a conserved SH3 domain near RhoGEF and PH domains, and a non-modular C-terminus with phosphorylation motifs. The obscurin gene also encodes two kinase domains, which are not part of the 800 kDa form of the protein, but is part of smaller spliced products that present in heart muscle. 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 2024334814  828 ITGYDGNLNELGKLLMQGSFNVWtdhkKGHSKVKDLARfkPMQRHLFLHEKAVLFCKKREENGEGYEkapSYSYKHSLNM 907
Cdd:cd13239      2 IENYPAPLQALGEPIRQGHFTVW----EEAPEVKTSSR--GHHRHVFLFKNCVVICKPKRDSRTDTV---TYVFKNKMKL 72

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 2024334814  908 AAVGITENVKGDAKKFEIWYNAREEV--YIIQAPTPEVKATWVNEIRKV 954
Cdd:cd13239     73 SDIDVKDTVEGDDRSFGLWHEHRGSVrkYTLQARSAIIKSSWLKDLRDL 121

Sec14p-like lipid-binding domain; Sec14p-like lipid-binding domains are found in secretory proteins, such as S. cerevisiae phosphatidylinositol transfer protein (Sec14p), and in lipid regulated proteins such as RhoGAPs, RhoGEFs and neurofibromin (NF1). SEC14 domain of Dbl is known to associate with G protein beta/gamma subunits.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   82 DIHDQLKKqfAYLSGGRGGDGCPVITF-PDYPAFSEIPEKEFQNVLTYL--TSIPSLRDAGIGFILVIDRRQDKWTS--- 155
Cdd:cd00170      3 ELLELLGG--IGYLGGRDKEGRPVLVFrAGWDPPKLLDLEELLRYLVYLleKALRELEEQVEGFVVIIDLKGFSLSNlsd 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024334814  156 ---VKASILRIAASFPGNLQLVLVLRPTGLIhRALSDIAFKFNRDEFKMKvpIIMLGS-VSELQGYIDKTQLTEDLGGT 230
Cdd:cd00170     81 lslLKKLLKILQDHYPERLKKIYIVNAPWIF-SALWKIVKPFLSEKTRKK--IVFLGSdLEELLEYIDPDQLPKELGGT 156

First Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the first SH3 domain of Tks5. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKnlTTGREGWIPANNL 1125
Cdd:cd12074      1 QYVVVSNYEKQENSEISLQAGEVVDVIEKNESGWWFVS--TAEEQGWVPATYL 51

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  532 YAHILNEDLKEHIQkvFQKQESMEEMFQKRQVS-------LKKLAAKQTRPVQPVAPRPEAFVKSPCTspgLQRDCVSNT 604
Cdd:COG5422    344 YDHRLRDSRIEIYQ--LRGYSDMRIAHNFPTSStsfenmgKATLTNSSSSTNEPATPKAEYNPNGVFT---LLTECYSST 418

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  605 ESgvLRKVNY-----RRGKSEMSELHQSRGG----STM-----DDEENLAVL----------------RQHVMNELIETE 654
Cdd:COG5422    419 CS--RDELCYsiscpRRLEQQARLHLKLMGGlkrnSSLaldkfDEEKNLWTLsvpkevweslpkqeikRQEAIYEVIYTE 496

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  655 RAYVEELlcvlEGYAAEMDNPLMAHLISPELQNKKDI--LFGNMEEIYHFHNRIF--LRELENYVEYPELVGRCFLDQME 730
Cdd:COG5422    497 RDFVKDL----EYLRDTWIKPLEESNIIPENARRNFIkhVFANINEIYAVNSKLLkaLTNRQCLSPIVNGIADIFLDYVP 572

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  731 DFQIYEKYCQNKP-------RSESLWRQFSdsIFFQECQR-KLDHKLSLDSYLLKPVQRITKYQLLLKEMLKYSK-NCEG 801
Cdd:COG5422    573 KFEPFIKYGASQPyakyefeREKSVNPNFA--RFDHEVERlDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDpDNPD 650

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814  802 AEDLQEALNSILGILKAVNdsmHQIAITGYDGNLNELGKLLM-------QGSFNVWTDHK-KGHSKVKDLARFKPMQR-- 871
Cdd:COG5422    651 TEDIPKVIDMLREFLSRLN---FESGKAENRGDLFHLNQQLLfkpeyvnLGLNDEYRKIIfKGVLKRKAKSKTDGSLRgd 727

                          410
                   ....*....|....*....
gi 2024334814  872 -HLFLHEKAVLFCKKREEN 889
Cdd:COG5422    728 iQFFLLDNMLLFCKAKAVN 746

First or N-terminal Src homology 3 domain of the p47phox subunit of NADPH oxidase, also called Neutrophil Cytosolic Factor 1; p47phox, or NCF1, is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR). This model characterizes the first SH3 domain (or N-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2024334814 1074 YTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKnlTTGREGWIPANNL 1125
Cdd:cd12021      2 YRAIADYEKSSKSEMALKTGDVVEVVEKSENGWWFCQ--LKAKRGWVPASYL 51

First Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also called SH3 and PX domain-containing protein 2B (SH3PXD2B) or HOFI, is a Src substrate and scaffolding protein that plays an important role in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. It is required in the formation of functional podosomes, EGF-induced membrane ruffling, and lamellipodia generation. It plays an important role in cellular attachment and cell spreading. Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. It contains an N-terminal Phox homology (PX) domain and four SH3 domains. This model characterizes the first SH3 domain of Tks4. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKnlTTGREGWIPANNL 1125
Cdd:cd12075      2 QYVVVANYQKQESSEISLYVGQVVDIIEKNESGWWFVS--TADEQGWVPATCL 52

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKNLtTGREGWIPAN 1123
Cdd:cd00174      1 YARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGELN-GGREGLFPAN 50

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 2024334814  1071 PGKYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKNLtTGREGWIPAN 1123
Cdd:smart00326    2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLG-RGKEGLFPSN 53

Second Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the second SH3 domain of Tks5. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2024334814 1073 KYTVVSDYEKGVSEEFAVKGGDLVQLIREGEDGLWYVKNLttGREGWIPANNL 1125
Cdd:cd12077      2 KYVTVQPYTSQGKDEIGFEKGVTVEVIQKNLEGWWYIRYL--GKEGWAPASYL 52

Src Homology 3 domain of fungal BOI-like proteins; This subfamily includes the Saccharomyces cerevisiae proteins BOI1 and BOI2, and similar proteins. They contain an N-terminal SH3 domain, a Sterile alpha motif (SAM), and a Pleckstrin homology (PH) domain at the C-terminus. BOI1 and BOI2 interact with the SH3 domain of Bem1p, a protein involved in bud formation. They promote polarized cell growth and participates in the NoCut signaling pathway, which is involved in the control of cytokinesis. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2024334814 1074 YTVVSDYEKGVSEEFAVKGGDLVQLI---REGEDGLWYVKNLTTGREGWIPAN 1123
Cdd:cd11886      2 LIVIHDFNARSEDELTLKPGDKIELIeddEEFGDGWYLGRNLRTGETGLFPVV 54

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024334814   368 EQNFREVKAALDIVS--ERLSAFTDVGNSCSHVEHILKDLANFEEKSCETVAKARMLASEGDAFIQSNHYAVDSIIPKCS 445
Cdd:smart00150    1 QQFLRDADELEAWLEekEQLLASEDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERLE 80

                            90       100
                    ....*....|....*....|.
gi 2024334814   446 ELHHLCDAFTTEMEQRRNVLN 466
Cdd:smart00150   81 ELNERWEELKELAEERRQKLE 101