Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982  838 AINGYVGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKHCLK 917
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1039795982  918 MEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 969
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 1039795982   128 AFLSGGRG--KDNAWIITFP--ENCNFRCIPEEVIAKVLNYLTSIARQSGSD---SRFTIILDRR-----LDTWASLKIS 195
Cdd:smart00516    7 AYIPGGRGydKDGRPVLIERagRFDLKSVTLEELLRYLVYVLEKILQEEKKTggiEGFTVIFDLKglsmsNPDLSVLRKI 86

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1039795982   196 LQKISASFPGSLHLVLVLRPTSFLqRTFTDIGFRFSQEDFMLKLPVVMLSSVSDLLTYIDDKQLTPELGGTLQ 268
Cdd:smart00516   87 LKILQDHYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

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 1039795982  838 AINGYVGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKHCLK 917
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1039795982  918 MEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 969
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 1039795982   657 VLNELIQTERAYVRELFTVLLGYRSEMDNPQMFdlmppLLRNKKDVLFGNMAEIYEFHNnIFMSRLEDCS----DAPERV 732
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERIeewdDSVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982   733 GPCFLERKDDFQMYAKYCQNKPRSELIWRKYSEC----AFFQECQRKLKH-RLGLDSYLLKPVQRITKYQLLLKELLKYS 807
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 1039795982   808 KEG-EGTTKLKEALDSMLELLKSVND 832
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 1039795982   128 AFLSGGRG--KDNAWIITFP--ENCNFRCIPEEVIAKVLNYLTSIARQSGSD---SRFTIILDRR-----LDTWASLKIS 195
Cdd:smart00516    7 AYIPGGRGydKDGRPVLIERagRFDLKSVTLEELLRYLVYVLEKILQEEKKTggiEGFTVIFDLKglsmsNPDLSVLRKI 86

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1039795982   196 LQKISASFPGSLHLVLVLRPTSFLqRTFTDIGFRFSQEDFMLKLPVVMLSSVSDLLTYIDDKQLTPELGGTLQ 268
Cdd:smart00516   87 LKILQDHYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982   869 TKMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI 944
Cdd:smart00233    8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTL 80

                            90       100
                    ....*....|....*....|..
gi 1039795982   945 YIvQAPNVDVKMLWLKEIRKIL 966
Cdd:smart00233   81 LL-QAESEEEREKWVEALRKAI 101

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 1039795982  402 QLWKFEQDFQEELLTKARIV---ILRGHKLASNHHYA-------LDLICQRCNELRYLSDilvneirTKRVQLSRTFKVH 471
Cdd:cd00176     37 ALLKKHEALEAELAAHEERVealNELGEQLIEEGHPDaeeiqerLEELNQRWEELRELAE-------ERRQRLEEALDLQ 109

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982  472 RLLQQARQC---CDQGECLLASQGMDKfqTKEDAQKALQDVDNFlQMAMPFINYDIESLQYEFDVLLSPELKAQMQNIQL 548
Cdd:cd00176    110 QFFRDADDLeqwLEEKEAALASEDLGK--DLESVEELLKKHKEL-EEELEAHEPRLKSLNELAEELLEEGHPDADEEIEE 186

                          170
                   ....*....|.
gi 1039795982  549 KLENIRSAFQN 559
Cdd:cd00176    187 KLEELNERWEE 197

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982  870 KMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI- 944
Cdd:pfam00169    9 KKGGGKKKSWKKRYFVLFDGSLLYYKDD-------KSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRTGERTGKr 81

                           90       100
                   ....*....|....*....|...
gi 1039795982  945 -YIVQAPNVDVKMLWLKEIRKIL 966
Cdd:pfam00169   82 tYLLQAESEEERKDWIKAIQSAI 104

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 1039795982  838 AINGYVGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKHCLK 917
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1039795982  918 MEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 969
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 1039795982   657 VLNELIQTERAYVRELFTVLLGYRSEMDNPQMFdlmppLLRNKKDVLFGNMAEIYEFHNnIFMSRLEDCS----DAPERV 732
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERIeewdDSVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982   733 GPCFLERKDDFQMYAKYCQNKPRSELIWRKYSEC----AFFQECQRKLKH-RLGLDSYLLKPVQRITKYQLLLKELLKYS 807
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 1039795982   808 KEG-EGTTKLKEALDSMLELLKSVND 832
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 1039795982  831 NDSMHQTAINGYVGNINELGKMVLQGSFNVWLGHRKGatkmkdfarfkpmQRHLFLYEKAVMFCK-RRFESGEGAdryps 909
Cdd:cd13242      8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKpKKTPGGKDV----- 69

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1039795982  910 YSFKHCLKMEDVGITEHVKGDNRKFEI--RYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 969
Cdd:cd13242     70 YIYKHSIKTSDIGLTENVGDSGLKFEIwfRRRKARDTYILQATSPEIKQAWTSDIAKLLWKQ 131

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 1039795982  841 GYVGNINELGKMVLQGSFNVwlghrkgaTKMKDFARFKPMQRHLFLYEKAVMFC-----KRRFESgegadryPSYSFKHC 915
Cdd:cd13241      6 GFDGKITAQGKLLLQGTLLV--------SEPSAGLLQKGKERRVFLFEQIIIFSeilgkKTQFSN-------PGYIYKNH 70

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1039795982  916 LKMEDVGITEHVKGDNRKFEIRYSEK---EEIYIVQAPNVDVKMLWLKEIRKILVQQKELMTA 975
Cdd:cd13241     71 IKVNKMSLEENVDGDPLRFALKSRDPnnpSETFILQAASPEVRQEWVDTINQILDTQRDFLKA 133

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 1039795982  841 GYVGNINELGKMVLQGSFNVWlghrkgatKMKDFARfKPMQRHLFLYEKAVMFCKRRFESgegaDRYPSYSFKHCLKMED 920
Cdd:cd13240      4 GCDEDLDSLGEVILQDSFQVW--------DPKQLIR-KGRERHVFLFELCLVFSKEVKDS----NGKSKYIYKSRLMTSE 70

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 1039795982  921 VGITEHVKGDNRKFEI---RYSEKEEIYIVQAPNVDVKMLWLKEIRKIL 966
Cdd:cd13240     71 IGVTEHIEGDPCKFALwtgRVPTSDNKIVLKASSLEVKQTWVKKLREVI 119

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982   869 TKMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI 944
Cdd:smart00233    8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTL 80

                            90       100
                    ....*....|....*....|..
gi 1039795982   945 YIvQAPNVDVKMLWLKEIRKIL 966
Cdd:smart00233   81 LL-QAESEEEREKWVEALRKAI 101

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 1039795982  844 GNINELGKMVLQGSFNVWlghrkgatkmkdFARFKPMQRHLFLYEKAVMFCKRRfESGEgaDRypSYS-FKHCLKMEDVG 922
Cdd:cd13325      1 GNIHKLGRLLRHDWFTVT------------DGEGKAKERYLFLFKSRILITKVR-RISE--DR--SVFiLKDIIRLPEVN 63

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1039795982  923 ITEHvKGDNRKFEIRYS-EKEEIY--IVQAPNVDVKMLWLKEIRK 964
Cdd:cd13325     64 VKQH-PDDERTFELQPKlPAFGILpiDFKAHKDEIKDYWLNEIEE 107

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 1039795982  402 QLWKFEQDFQEELLTKARIV---ILRGHKLASNHHYA-------LDLICQRCNELRYLSDilvneirTKRVQLSRTFKVH 471
Cdd:cd00176     37 ALLKKHEALEAELAAHEERVealNELGEQLIEEGHPDaeeiqerLEELNQRWEELRELAE-------ERRQRLEEALDLQ 109

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982  472 RLLQQARQC---CDQGECLLASQGMDKfqTKEDAQKALQDVDNFlQMAMPFINYDIESLQYEFDVLLSPELKAQMQNIQL 548
Cdd:cd00176    110 QFFRDADDLeqwLEEKEAALASEDLGK--DLESVEELLKKHKEL-EEELEAHEPRLKSLNELAEELLEEGHPDADEEIEE 186

                          170
                   ....*....|.
gi 1039795982  549 KLENIRSAFQN 559
Cdd:cd00176    187 KLEELNERWEE 197

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982  870 KMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI- 944
Cdd:pfam00169    9 KKGGGKKKSWKKRYFVLFDGSLLYYKDD-------KSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRTGERTGKr 81

                           90       100
                   ....*....|....*....|...
gi 1039795982  945 -YIVQAPNVDVKMLWLKEIRKIL 966
Cdd:pfam00169   82 tYLLQAESEEERKDWIKAIQSAI 104

Vav pleckstrin homology (PH) domain; Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid- dependent regulator of GEF activity. Vavs bind RhoGTPases including Rac1, RhoA, RhoG, and Cdc42, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD. 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.polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. 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 kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039795982  867 GATKMKDFARFKPMQRHLFLYEKAVMFCKRRFESgegadrypSYSFKHCLKMEDVGITEHVKGDNRKFEIRYS------- 939
Cdd:cd01223     23 GELKIKSHEDQKKKDRYAFLFDKVLLICKSLRGD--------QYEYKEIINLSEYRIEDDPSRRTLKRDKRWSyqfllvh 94

                           90       100
                   ....*....|....*....|....*.
gi 1039795982  940 -EKEEIYIVQAPNVDVKMLWLKEIRK 964
Cdd:cd01223     95 kQGKTAYTLYAKTEELKKKWMEAIEM 120