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 1622884827  790 AITGYDGNLGDLGKLLMQGSFSVWTDHKRGHTKvkELARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKQSLN 869
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884827  870 MAAVGITENVKGDAKKFEIWYNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQ 921
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

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 1622884827    50 LKKRFAYLSGGRGQD--GSPVITFPDY--PAFSEIPDKEFQNVMTYLTSIPSLQDAGI---GFILVIDRRRDKWTSVKAS 122
Cdd:smart00516    2 LELLKAYIPGGRGYDkdGRPVLIERAGrfDLKSVTLEELLRYLVYVLEKILQEEKKTGgieGFTVIFDLKGLSMSNPDLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622884827   123 VLRIAAS-----FPANLQLVLVLRPTGFFqRTLSDIAFKFNRDDFKMKVPVIMLSSVPDLHGYIDKSQLTEDLGGTLD 195
Cdd:smart00516   82 VLRKILKilqdhYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

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
                   ....*....|....*....|....*....|....*
gi 1622884827 1033 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLW 1067
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQW 35

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 1622884827  790 AITGYDGNLGDLGKLLMQGSFSVWTDHKRGHTKvkELARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKQSLN 869
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884827  870 MAAVGITENVKGDAKKFEIWYNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQ 921
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 1622884827   609 VMSELLDTERAYVEELLCVLEGYAAEMDNPLMahLLStglHNKKDVLFGNMEEIYHFHnRIFLRELENYIDC----PELV 684
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELK--LLS---PNELETLFGNIEEIYEFH-RDFLDELEERIEEwddsVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827   685 GRCFLERMEDFQIYEKYCQNKPRSESLWRQCSDCPFFQECQRKLDHK-----LSLDSYLLKPVQRITKYQLLLKEMLKYS 759
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSpqcrrLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 1622884827   760 K-NCEGAEDLQEALSSILGILKAVND 784
Cdd:smart00325  155 PeDHEDREDLKKALKAIKELANQVNE 180

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 1622884827    50 LKKRFAYLSGGRGQD--GSPVITFPDY--PAFSEIPDKEFQNVMTYLTSIPSLQDAGI---GFILVIDRRRDKWTSVKAS 122
Cdd:smart00516    2 LELLKAYIPGGRGYDkdGRPVLIERAGrfDLKSVTLEELLRYLVYVLEKILQEEKKTGgieGFTVIFDLKGLSMSNPDLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622884827   123 VLRIAAS-----FPANLQLVLVLRPTGFFqRTLSDIAFKFNRDDFKMKVPVIMLSSVPDLHGYIDKSQLTEDLGGTLD 195
Cdd:smart00516   82 VLRKILKilqdhYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

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 1622884827  326 QLRHFEQGFREVKAILDAVCQKIATfTDIGNSLAHVEHLLRDLASFEEKSGVSVERARALSLDGEQLIENKHYAVDSIRP 405
Cdd:cd00176      1 KLQQFLRDADELEAWLSEKEELLSS-TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQE 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  406 KCQELRHLCDQFSSEIVRRRGLLSKSLELHRRLETS---LKWCDEGIYLLASQPVDKcqSQDGAEAALQEIEKFLET--S 480
Cdd:cd00176     80 RLEELNQRWEELRELAEERRQRLEEALDLQQFFRDAddlEQWLEEKEAALASEDLGK--DLESVEELLKKHKELEEEleA 157

                          170       180       190
                   ....*....|....*....|....*....|...
gi 1622884827  481 AENKIQELNTIYKEYESILNQDLMEHVRKVFQK 513
Cdd:cd00176    158 HEPRLKSLNELAEELLEEGHPDADEEIEEKLEE 190

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 1622884827   45 DIQDQLKKrfAYLSGGRGQDGSPVITFPDYPAFSEIPDKE--FQNVMTYLTSIPSLQDAGI-GFILVIDRRRDKWTS--- 118
Cdd:cd00170      3 ELLELLGG--IGYLGGRDKEGRPVLVFRAGWDPPKLLDLEelLRYLVYLLEKALRELEEQVeGFVVIIDLKGFSLSNlsd 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622884827  119 ---VKASVLRIAASFPANLQLVLVLRPTGFFqRTLSDIAFKFNRDDFKMKVpVIMLSSVPDLHGYIDKSQLTEDLGGT 193
Cdd:cd00170     81 lslLKKLLKILQDHYPERLKKIYIVNAPWIF-SALWKIVKPFLSEKTRKKI-VFLGSDLEELLEYIDPDQLPKELGGT 156

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827   328 RHFEQGFREVKAILDAVcQKIATFTDIGNSLAHVEHLLRDLASFEEKSGVSVERARALSLDGEQLIENKHYAVDSIRPKC 407
Cdd:smart00150    1 QQFLRDADELEAWLEEK-EQLLASEDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERL 79

                            90       100
                    ....*....|....*....|.
gi 1622884827   408 QELRHLCDQFSSEIVRRRGLL 428
Cdd:smart00150   80 EELNERWEELKELAEERRQKL 100

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  604 ILRRHVMSELLDTERAYVEELLCVLEGYaaemdnplMAHLLSTGL---HNKKDVL---FGNMEEIYHFHNRIF--LRELE 675
Cdd:COG5422    483 IKRQEAIYEVIYTERDFVKDLEYLRDTW--------IKPLEESNIipeNARRNFIkhvFANINEIYAVNSKLLkaLTNRQ 554

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  676 NYIDCPELVGRCFLERMEDFQIYEKYCQNKPRSE-SLWRQCSDCPFFQecqrKLDH---------KLSLDSYLLKPVQRI 745
Cdd:COG5422    555 CLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKyEFEREKSVNPNFA----RFDHeverldesrKLELDGYLTKPTTRL 630

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  746 TKYQLLLKEMLKYSKncEGAEDLQEalssILGILKAVNDSMHLIAI-TGYDGNLGDLGKLLMQGSFSVWT------DHKR 818
Cdd:COG5422    631 ARYPLLLEEVLKFTD--PDNPDTED----IPKVIDMLREFLSRLNFeSGKAENRGDLFHLNQQLLFKPEYvnlglnDEYR 704

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|..
gi 1622884827  819 -----GHTKVKELARFKPMQR---HLFLHEKAVLFCKKREEN 852
Cdd:COG5422    705 kiifkGVLKRKAKSKTDGSLRgdiQFFLLDNMLLFCKAKAVN 746

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 1622884827  790 AITGYDGNLGDLGKLLMQGSFSVWTDHKRGHTKvkELARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKQSLN 869
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884827  870 MAAVGITENVKGDAKKFEIWYNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQ 921
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 1622884827   609 VMSELLDTERAYVEELLCVLEGYAAEMDNPLMahLLStglHNKKDVLFGNMEEIYHFHnRIFLRELENYIDC----PELV 684
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELK--LLS---PNELETLFGNIEEIYEFH-RDFLDELEERIEEwddsVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827   685 GRCFLERMEDFQIYEKYCQNKPRSESLWRQCSDCPFFQECQRKLDHK-----LSLDSYLLKPVQRITKYQLLLKEMLKYS 759
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSpqcrrLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 1622884827   760 K-NCEGAEDLQEALSSILGILKAVND 784
Cdd:smart00325  155 PeDHEDREDLKKALKAIKELANQVNE 180

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 1622884827    50 LKKRFAYLSGGRGQD--GSPVITFPDY--PAFSEIPDKEFQNVMTYLTSIPSLQDAGI---GFILVIDRRRDKWTSVKAS 122
Cdd:smart00516    2 LELLKAYIPGGRGYDkdGRPVLIERAGrfDLKSVTLEELLRYLVYVLEKILQEEKKTGgieGFTVIFDLKGLSMSNPDLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622884827   123 VLRIAAS-----FPANLQLVLVLRPTGFFqRTLSDIAFKFNRDDFKMKVPVIMLSSVPDLHGYIDKSQLTEDLGGTLD 195
Cdd:smart00516   82 VLRKILKilqdhYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

p63RhoGEF pleckstrin homology (PH) domain, repeat 2; The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric G protein, Galphaq and linking Galphaq-coupled receptors (GPCRs) to the activation of RhoA. The Dbl(DH) and PH domains of p63RhoGEF interact with the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. 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 1622884827  793 GYDGNLGDLGKLLMQGSFSVwtdhkrghTKVKELARFKPMQRHLFLHEKAVLFC----KKREENGegyekaPSYSYKQSL 868
Cdd:cd13241      6 GFDGKITAQGKLLLQGTLLV--------SEPSAGLLQKGKERRVFLFEQIIIFSeilgKKTQFSN------PGYIYKNHI 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1622884827  869 NMAAVGITENVKGDAKKFEIW---YNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQL 922
Cdd:cd13241     72 KVNKMSLEENVDGDPLRFALKsrdPNNPSETFILQAASPEVRQEWVDTINQILDTQR 128

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 1622884827  791 ITGYDGNLGDLGKLLMQGSFSVWtDHKRGHTKVKElarfkpmqRHLFLHEKAVLFCKKrEENGEGYEKapsYSYKQSLNM 870
Cdd:cd13240      2 LEGCDEDLDSLGEVILQDSFQVW-DPKQLIRKGRE--------RHVFLFELCLVFSKE-VKDSNGKSK---YIYKSRLMT 68

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1622884827  871 AAVGITENVKGDAKKFEIW---YNAREEVYIVQAPTPEIKAAWVNEIRKVL 918
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 1622884827  791 ITGYDGNLGDLGKLLMQGSFSVWTDH------KRGHtkvkelarfkpmQRHLFLHEKAVLFCKKREENGEGYEkapSYSY 864
Cdd:cd13239      2 IENYPAPLQALGEPIRQGHFTVWEEApevktsSRGH------------HRHVFLFKNCVVICKPKRDSRTDTV---TYVF 66

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1622884827  865 KQSLNMAAVGITENVKGDAKKFEIWYNAREEV--YIVQAPTPEIKAAWVNEIRKV 917
Cdd:cd13239     67 KNKMKLSDIDVKDTVEGDDRSFGLWHEHRGSVrkYTLQARSAIIKSSWLKDLRDL 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 1622884827   45 DIQDQLKKrfAYLSGGRGQDGSPVITFPDYPAFSEIPDKE--FQNVMTYLTSIPSLQDAGI-GFILVIDRRRDKWTS--- 118
Cdd:cd00170      3 ELLELLGG--IGYLGGRDKEGRPVLVFRAGWDPPKLLDLEelLRYLVYLLEKALRELEEQVeGFVVIIDLKGFSLSNlsd 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622884827  119 ---VKASVLRIAASFPANLQLVLVLRPTGFFqRTLSDIAFKFNRDDFKMKVpVIMLSSVPDLHGYIDKSQLTEDLGGT 193
Cdd:cd00170     81 lslLKKLLKILQDHYPERLKKIYIVNAPWIF-SALWKIVKPFLSEKTRKKI-VFLGSDLEELLEYIDPDQLPKELGGT 156

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827   328 RHFEQGFREVKAILDAVcQKIATFTDIGNSLAHVEHLLRDLASFEEKSGVSVERARALSLDGEQLIENKHYAVDSIRPKC 407
Cdd:smart00150    1 QQFLRDADELEAWLEEK-EQLLASEDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERL 79

                            90       100
                    ....*....|....*....|.
gi 1622884827   408 QELRHLCDQFSSEIVRRRGLL 428
Cdd:smart00150   80 EELNERWEELKELAEERRQKL 100

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 1622884827  821 TKVKELARFKPMQRHLFLHEKAVLFCKKREENgegyekapSYSYKQSLNMAA-VGITENVKGDAK-KFEIWyNAREEVYI 898
Cdd:cd00821      6 LKRGGGGLKSWKKRWFVLFEGVLLYYKSKKDS--------SYKPKGSIPLSGiLEVEEVSPKERPhCFELV-TPDGRTYY 76

                           90
                   ....*....|....*.
gi 1622884827  899 VQAPTPEIKAAWVNEI 914
Cdd:cd00821     77 LQADSEEERQEWLKAL 92

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  604 ILRRHVMSELLDTERAYVEELLCVLEGYaaemdnplMAHLLSTGL---HNKKDVL---FGNMEEIYHFHNRIF--LRELE 675
Cdd:COG5422    483 IKRQEAIYEVIYTERDFVKDLEYLRDTW--------IKPLEESNIipeNARRNFIkhvFANINEIYAVNSKLLkaLTNRQ 554

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  676 NYIDCPELVGRCFLERMEDFQIYEKYCQNKPRSE-SLWRQCSDCPFFQecqrKLDH---------KLSLDSYLLKPVQRI 745
Cdd:COG5422    555 CLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKyEFEREKSVNPNFA----RFDHeverldesrKLELDGYLTKPTTRL 630

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  746 TKYQLLLKEMLKYSKncEGAEDLQEalssILGILKAVNDSMHLIAI-TGYDGNLGDLGKLLMQGSFSVWT------DHKR 818
Cdd:COG5422    631 ARYPLLLEEVLKFTD--PDNPDTED----IPKVIDMLREFLSRLNFeSGKAENRGDLFHLNQQLLFKPEYvnlglnDEYR 704

                          250       260       270       280
                   ....*....|....*....|....*....|....*....|..
gi 1622884827  819 -----GHTKVKELARFKPMQR---HLFLHEKAVLFCKKREEN 852
Cdd:COG5422    705 kiifkGVLKRKAKSKTDGSLRgdiQFFLLDNMLLFCKAKAVN 746

Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain; PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction. Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterized by panic attacks and anticipatory anxiety. 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 1622884827  766 EDLQEALSSILGILKAVND-------SMHL----IAITGYDG-NLGDLGKLLMQGSFSVwtdhkRGHTKvkelarfkpmQ 833
Cdd:cd13243      2 SVVEEALDTMTQVAWHINDmkrkhehAVRVqeiqSLLDGWEGpELTTYGDLVLEGTFRM-----AGAKN----------E 66

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884827  834 RHLFLHEKAVLFCKKREENGegyekapsYSYKQSLNMAAVGITENVKGDAKKFEIW-YNAREEVYIVQAPTPEIKAAWVN 912
Cdd:cd13243     67 RLLFLFDKMLLITKKREDGI--------LQYKTHIMCSNLMLSESIPKEPLSFQVLpFDNPKLQYTLQAKNQEQKRLWTQ 138

                   ....*.
gi 1622884827  913 EIRKVL 918
Cdd:cd13243    139 EIKRLI 144

unc89 pleckstrin homology (PH) domain; unc89 is a myofibrillar protein. unc89-B the largest isoform is composed of 53 immunoglobulin (Ig) domains, 2 Fn3 domains, a triplet of SH3, DH and PH domains at its N-terminus, and 2 protein kinase domains (PK1 and PK2) at its C-terminus. unc-89 mutants display disorganization of muscle A-bands, and usually lack M-lines. The COOH-terminal region of obscurin, the human homolog of unc89, interacts via two specific Ig-like domains with the NH(2)-terminal Z-disk region of titin, a protein that connects the Z line to the M line in the sarcomere and contributes to the contraction of striated muscle. obscurin is also thought to be involved in Ca2+/calmodulin via its IQ domains, as well as G protein-coupled signal transduction in the sarcomere via its RhoGEF/DH domain. The DH-PH region of OBSCN and unc89, the C. elegans homolog, has exchange activity for RhoA and Rho-1 respectively, but not for the small GTPases homologous to Cdc42 or Rac. 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 1622884827  796 GNLGDLGKLLMQGSFSVWTdhkrghtkvkelARFKPMQRHLFLHEKAVLFCKKREENgegyEKAPSYSYKQSLNMAAVGI 875
Cdd:cd13325      1 GNIHKLGRLLRHDWFTVTD------------GEGKAKERYLFLFKSRILITKVRRIS----EDRSVFILKDIIRLPEVNV 64

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1622884827  876 tENVKGDAKKFEIWYNA---REEVYIVQAPTPEIKAAWVNEIRK 916
Cdd:cd13325     65 -KQHPDDERTFELQPKLpafGILPIDFKAHKDEIKDYWLNEIEE 107

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. 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
                   ....*....|....*....|....*....|....*....
gi 1622884827 1034 YTVVADHEKGGPDALVVRSGDVVELVQQ-----GDEGLW 1067
Cdd:cd12058      2 WTALYDYEASGEDELSLRRGDVVEVLSQdaavsGDDGWW 40

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. 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
                   ....*....|....*....|....*....|....*....
gi 1622884827 1034 YTVVADHEKGGPDALVVRSGDVVELVQQ-----GDEGLW 1067
Cdd:cd12059      2 WTAVFDYEASAEDELTLRRGDRVEVLSKdsavsGDEGWW 40