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 4504335  1461 MLEGFDENLDVQGELILQDAFQVWDPKSLIRKGRERHLFLFEISLVFSKEIKDSSGHTKYVYKNKLLTSELGVTEHVEGD 1540
Cdd:cd13240    1 LLEGCDEDLDSLGEVILQDSFQVWDPKQLIRKGRERHVFLFELCLVFSKEVKDSNGKSKYIYKSRLMTSEIGVTEHIEGD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 4504335  1541 PCKFALWSGRTPSSDNKTVLKASNIETKQEWIKNIREVIQERI 1583
Cdd:cd13240   81 PCKFALWTGRVPTSDNKIVLKASSLEVKQTWVKKLREVIQERI 123

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 4504335       39 LKEKVAFVSGGR--DKRGGPILTFPARS--NHDRIRQEDLRKLVTYLASVPS---EDVCKRGFTVIIDMRGSK-----WD 106
Cdd:smart00516    2 LELLKAYIPGGRgyDKDGRPVLIERAGRfdLKSVTLEELLRYLVYVLEKILQeekKTGGIEGFTVIFDLKGLSmsnpdLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4504335      107 LIKPLLKTLQEAFPAEIHVALIIKPDNFWQ---KQKTNFGSSKFIFETSMVS---VEGLTKLVDPSQLTEEFDGSLD 177
Cdd:smart00516   82 VLRKILKILQDHYPERLGKVYIINPPWFFRvlwKIIKPFLDEKTREKIRFVGndsKEELLEYIDKEQLPEELGGTLD 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 4504335   891 QLRHLQAEVKQVLGWIRNGESMLnASLVNASSLSEAEQLQREHEQFQlaieslfhaTSLQKTHQSALQVQQKAEVLLQAG 970
Cdd:cd00176    1 KLQQFLRDADELEAWLSEKEELL-SSTDYGDDLESVEALLKKHEALE---------AELAAHEERVEALNELGEQLIEEG 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   971 HYDADAIRECAEKVALHWQQLMLKMEDRLKLVNASVAFYKTSEQVCSVlesleqeyrrdEDWCGGRDKLGPAAEIDHVIP 1050
Cdd:cd00176   71 HPDAEEIQERLEELNQRWEELRELAEERRQRLEEALDLQQFFRDADDL-----------EQWLEEKEAALASEDLGKDLE 139

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4504335  1051 LISKHLEQKEAFLKACTlarrNAEVFLKYIHRNNVSMpsVASHTRGPEQQVKAILSELLQRENRVLHFWTLKKRRLDQC 1129
Cdd:cd00176  140 SVEELLKKHKELEEELE----AHEPRLKSLNELAEEL--LEEGHPDADEEIEEKLEELNERWEELLELAEERQKKLEEA 212

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 4504335   311 QLRLFEQDAEKMFDWISHnKELFLQShTEIGVSYQYALDLQTQHNHFAMNSMNAYVNINRIMSVASRLSEAGHYASQQIK 390
Cdd:cd00176    1 KLQQFLRDADELEAWLSE-KEELLSS-TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQ 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   391 QISTQLDQEWKSFAAALDERSTILAMSAVFHQKAEQFLSgVDAWC----KMCSEGGLPSEMQDLELAIHHHQTLYEQVTQ 466
Cdd:cd00176   79 ERLEELNQRWEELRELAEERRQRLEEALDLQQFFRDADD-LEQWLeekeAALASEDLGKDLESVEELLKKHKELEEELEA 157

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   467 AytevSQDGKALLDVLQRPLSPGNSESLTATAnyskavhqvlDVVHEVLHHQRRLESIWQHRKVRLHQRL 536
Cdd:cd00176  158 H----EPRLKSLNELAEELLEEGHPDADEEIE----------EKLEELNERWEELLELAEERQKKLEEAL 213

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 4504335  1461 MLEGFDENLDVQGELILQDAFQVWDPKSLIRKGRERHLFLFEISLVFSKEIKDSSGHTKYVYKNKLLTSELGVTEHVEGD 1540
Cdd:cd13240    1 LLEGCDEDLDSLGEVILQDSFQVWDPKQLIRKGRERHVFLFELCLVFSKEVKDSNGKSKYIYKSRLMTSEIGVTEHIEGD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 4504335  1541 PCKFALWSGRTPSSDNKTVLKASNIETKQEWIKNIREVIQERI 1583
Cdd:cd13240   81 PCKFALWTGRVPTSDNKIVLKASSLEVKQTWVKKLREVIQERI 123

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 4504335     1285 IMAELLQTEKAYVRDLHECLETYLWEMTSGVEEIPPgilNKEHIIFGNIQEIYDFHNnIFLKELEKY----EQLPEDVGH 1360
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLLSP---NELETLFGNIEEIYEFHR-DFLDELEERieewDDSVERIGD 76

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335     1361 CFVTWADKFQMYVTYCKNKPDSNQLI--LEHAGTFFDEIQQRHGLAN----SISSYLIKPVQRITKYQLLLKELLTCCEE 1434
Cdd:smart00325   77 VFLKLEEFFKIYSEYCSNHPDALELLkkLKKNPRFQKFLKEIESSPQcrrlTLESLLLKPVQRLTKYPLLLKELLKHTPE 156

                           170       180
                    ....*....|....*....|....
gi 4504335     1435 G---KGELKDGLEVMLSVPKKAND 1455
Cdd:smart00325  157 DhedREDLKKALKAIKELANQVNE 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 4504335       39 LKEKVAFVSGGR--DKRGGPILTFPARS--NHDRIRQEDLRKLVTYLASVPS---EDVCKRGFTVIIDMRGSK-----WD 106
Cdd:smart00516    2 LELLKAYIPGGRgyDKDGRPVLIERAGRfdLKSVTLEELLRYLVYVLEKILQeekKTGGIEGFTVIFDLKGLSmsnpdLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4504335      107 LIKPLLKTLQEAFPAEIHVALIIKPDNFWQ---KQKTNFGSSKFIFETSMVS---VEGLTKLVDPSQLTEEFDGSLD 177
Cdd:smart00516   82 VLRKILKILQDHYPERLGKVYIINPPWFFRvlwKIIKPFLDEKTREKIRFVGndsKEELLEYIDKEQLPEELGGTLD 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 4504335   537 QLCVFQQDVQQVLDWIENHGEAFLSkhTGVGKSLHRARALQKRHDDFEEVAQNTYTNADKLLEAAEQLAQTGECDPEEIY 616
Cdd:cd00176    1 KLQQFLRDADELEAWLSEKEELLSS--TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQ 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   617 KAARHLEVRIQDFVRRVEQRKLLLDMSV---SFHTHTKELWTWMEDLQKEMLEDVCADSVDAVQELIKQFQQQQtATLDA 693
Cdd:cd00176   79 ERLEELNQRWEELRELAEERRQRLEEALdlqQFFRDADDLEQWLEEKEAALASEDLGKDLESVEELLKKHKELE-EELEA 157

                        170       180
                 ....*....|....*....|....*
gi 4504335   694 TLNVIKEGEDLIQQLRSAPPSLGEP 718
Cdd:cd00176  158 HEPRLKSLNELAEELLEEGHPDADE 182

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 4504335      54 GGPILTFPARS-NHDRIRQEDLRKLVTYLASVPSEDVCKRGFTVIIDMRGS------KWDLIKPLLKTLQEAFPAEIHVA 126
Cdd:pfam13716    1 GRPVLVFISKLlPSRPASLDDLDRLLFYLLKTLSEKLKGKPFVVVVDHTGVtsenfpSLSFLKKAYDLLPRAFKKNLKAV 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335     127 LIIKPDNFWQKQ----KTNFGSSKFIFETSMVS-VEGLTKLVDPSQLTEEFDGSLDYNHE 181
Cdd:pfam13716   81 YVVHPSTFLRTFlktlGSLLGSKKLRKKVHYVSsLSELWEGIDREQLPTELPGVLSYDEE 140

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 4504335   311 QLRLFEQDAEKMFDWISHnKELFLQShTEIGVSYQYALDLQTQHNHFAMNSMNAYVNINRIMSVASRLSEAGHYASQQIK 390
Cdd:cd00176    1 KLQQFLRDADELEAWLSE-KEELLSS-TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQ 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   391 QISTQLDQEWKSFAAALDERSTILAMSAVFHQKAEQFLSgVDAWC----KMCSEGGLPSEMQDLELAIHHHQTLYEQVTQ 466
Cdd:cd00176   79 ERLEELNQRWEELRELAEERRQRLEEALDLQQFFRDADD-LEQWLeekeAALASEDLGKDLESVEELLKKHKELEEELEA 157

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   467 AytevSQDGKALLDVLQRPLSPGNSESLTATAnyskavhqvlDVVHEVLHHQRRLESIWQHRKVRLHQRL 536
Cdd:cd00176  158 H----EPRLKSLNELAEELLEEGHPDADEEIE----------EKLEELNERWEELLELAEERQKKLEEAL 213

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335      893 RHLQAEVKQVLGWIRNGESMLnASLVNASSLSEAEQLQREHEQFQlaieslfhaTSLQKTHQSALQVQQKAEVLLQAGHY 972
Cdd:smart00150    1 QQFLRDADELEAWLEEKEQLL-ASEDLGKDLESVEALLKKHEAFE---------AELEAHEERVEALNELGEQLIEEGHP 70

                            90       100
                    ....*....|....*....|....*...
gi 4504335      973 DADAIRECAEKVALHWQQLMLKMEDRLK 1000
Cdd:smart00150   71 DAEEIEERLEELNERWEELKELAEERRQ 98

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335      315 FEQDAEKMFDWIShNKELFLQShTEIGVSYQYALDLQTQHNHFAMNSMNAYVNINRIMSVASRLSEAGHYASQQIKQIST 394
Cdd:smart00150    3 FLRDADELEAWLE-EKEQLLAS-EDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERLE 80

                            90       100
                    ....*....|....*....|
gi 4504335      395 QLDQEWKSFAAALDERSTIL 414
Cdd:smart00150   81 ELNERWEELKELAEERRQKL 100

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335    1494 RERHLFLFEISLVFSKeikDSSGHTKYVYKNKLLTSELGVTEHVEGD----PCKFALWSGrTPSSDNKTVLKASNIETKQ 1569
Cdd:pfam00169   19 KKRYFVLFDGSLLYYK---DDKSGKSKEPKGSISLSGCEVVEVVASDspkrKFCFELRTG-ERTGKRTYLLQAESEEERK 94

                           90
                   ....*....|
gi 4504335    1570 EWIKNIREVI 1579
Cdd:pfam00169   95 DWIKAIQSAI 104

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335     890 LQLRHLQAEVKQVLGWIRNGESMLnASLVNASSLSEAEQLQREHEQFQLAIESlfHATSLQkthqsalQVQQKAEVLLQA 969
Cdd:pfam00435    1 LLLQQFFRDADDLESWIEEKEALL-SSEDYGKDLESVQALLKKHKALEAELAA--HQDRVE-------ALNELAEKLIDE 70

                           90       100
                   ....*....|....*....|..
gi 4504335     970 GHYDADAIRECAEKVALHWQQL 991
Cdd:pfam00435   71 GHYASEEIQERLEELNERWEQL 92

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335     1135 FERSAKQALDWIQETGEFYLSTHTSTGETTEETqeLLKEYGEFRVPAKQTKEKVKLLIQLADSFVEKGHIHATEIRKWVT 1214
Cdd:smart00150    3 FLRDADELEAWLEEKEQLLASEDLGKDLESVEA--LLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERLE 80

                            90       100
                    ....*....|....*....|.
gi 4504335     1215 TVDKHYRDFSLRMGKYRYSLE 1235
Cdd:smart00150   81 ELNERWEELKELAEERRQKLE 101

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 4504335  1461 MLEGFDENLDVQGELILQDAFQVWDPKSLIRKGRERHLFLFEISLVFSKEIKDSSGHTKYVYKNKLLTSELGVTEHVEGD 1540
Cdd:cd13240    1 LLEGCDEDLDSLGEVILQDSFQVWDPKQLIRKGRERHVFLFELCLVFSKEVKDSNGKSKYIYKSRLMTSEIGVTEHIEGD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 4504335  1541 PCKFALWSGRTPSSDNKTVLKASNIETKQEWIKNIREVIQERI 1583
Cdd:cd13240   81 PCKFALWTGRVPTSDNKIVLKASSLEVKQTWVKKLREVIQERI 123

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 4504335     1285 IMAELLQTEKAYVRDLHECLETYLWEMTSGVEEIPPgilNKEHIIFGNIQEIYDFHNnIFLKELEKY----EQLPEDVGH 1360
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLLSP---NELETLFGNIEEIYEFHR-DFLDELEERieewDDSVERIGD 76

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335     1361 CFVTWADKFQMYVTYCKNKPDSNQLI--LEHAGTFFDEIQQRHGLAN----SISSYLIKPVQRITKYQLLLKELLTCCEE 1434
Cdd:smart00325   77 VFLKLEEFFKIYSEYCSNHPDALELLkkLKKNPRFQKFLKEIESSPQcrrlTLESLLLKPVQRLTKYPLLLKELLKHTPE 156

                           170       180
                    ....*....|....*....|....
gi 4504335     1435 G---KGELKDGLEVMLSVPKKAND 1455
Cdd:smart00325  157 DhedREDLKKALKAIKELANQVNE 180

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 4504335  1459 VSMLEGFDENLDVQGELILQDAFQVWDPKS-LIRKGRERHLFLFEISLVFSKEI--KDSSGHTKYVYKNKLLTSELGVTE 1535
Cdd:cd13241    1 VGRLQGFDGKITAQGKLLLQGTLLVSEPSAgLLQKGKERRVFLFEQIIIFSEILgkKTQFSNPGYIYKNHIKVNKMSLEE 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335  1536 HVEGDPCKFALWSgRTPSSDNKT-VLKASNIETKQEWIKNIREVIQERIIHLKgALKEPL 1594
Cdd:cd13241   81 NVDGDPLRFALKS-RDPNNPSETfILQAASPEVRQEWVDTINQILDTQRDFLK-ALQSPI 138

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 4504335  1454 NDAMHVSMLEGFDENLDVQGELILQDAFQVWDPksliRKGRERHLFLFEISLVFSKEIKDSSGHTKYVYKNKLLTSELGV 1533
Cdd:cd13242    8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQG----RKKCLRHVFLFEDLILFSKPKKTPGGKDVYIYKHSIKTSDIGL 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 4504335  1534 TEHVEGDPCKFALWSGRTPSSDNkTVLKASNIETKQEWIKNIREVIQERIIHLK 1587
Cdd:cd13242   84 TENVGDSGLKFEIWFRRRKARDT-YILQATSPEIKQAWTSDIAKLLWKQAIRNR 136

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 4504335  1461 MLEGFDENLDVQGELILQDAFQVWDPKSLIR---KGRERHLFLFEISLVFSKEIKDSSGHTK-YVYKNKLLTSELGVTEH 1536
Cdd:cd13239    1 LIENYPAPLQALGEPIRQGHFTVWEEAPEVKtssRGHHRHVFLFKNCVVICKPKRDSRTDTVtYVFKNKMKLSDIDVKDT 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 4504335  1537 VEGDPCKFALWSGRTpSSDNKTVLKASNIETKQEWIKNIREvIQER 1582
Cdd:cd13239   81 VEGDDRSFGLWHEHR-GSVRKYTLQARSAIIKSSWLKDLRD-LQQR 124

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 4504335   537 QLCVFQQDVQQVLDWIENHGEAFLSkhTGVGKSLHRARALQKRHDDFEEVAQNTYTNADKLLEAAEQLAQTGECDPEEIY 616
Cdd:cd00176    1 KLQQFLRDADELEAWLSEKEELLSS--TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQ 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335   617 KAARHLEVRIQDFVRRVEQRKLLLDMSV---SFHTHTKELWTWMEDLQKEMLEDVCADSVDAVQELIKQFQQQQtATLDA 693
Cdd:cd00176   79 ERLEELNQRWEELRELAEERRQRLEEALdlqQFFRDADDLEQWLEEKEAALASEDLGKDLESVEELLKKHKELE-EELEA 157

                        170       180
                 ....*....|....*....|....*
gi 4504335   694 TLNVIKEGEDLIQQLRSAPPSLGEP 718
Cdd:cd00176  158 HEPRLKSLNELAEELLEEGHPDADE 182

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 4504335      54 GGPILTFPARS-NHDRIRQEDLRKLVTYLASVPSEDVCKRGFTVIIDMRGS------KWDLIKPLLKTLQEAFPAEIHVA 126
Cdd:pfam13716    1 GRPVLVFISKLlPSRPASLDDLDRLLFYLLKTLSEKLKGKPFVVVVDHTGVtsenfpSLSFLKKAYDLLPRAFKKNLKAV 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504335     127 LIIKPDNFWQKQ----KTNFGSSKFIFETSMVS-VEGLTKLVDPSQLTEEFDGSLDYNHE 181
Cdd:pfam13716   81 YVVHPSTFLRTFlktlGSLLGSKKLRKKVHYVSsLSELWEGIDREQLPTELPGVLSYDEE 140