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 1907202371 595 ITKYQlllkGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKH 674
Cdd:cd01227     2 ITGYD----GNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKN 71

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1907202371 675 CLKMEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 729
Cdd:cd01227    72 SLNTTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

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 1907202371 186 QDFQEAVTQVEFLLSQQREL---GDITGNLAQVKQRLKKLEILDDKSQELLTKARIVILRGHKLASNHHYA-------LD 255
Cdd:cd00176     3 QQFLRDADELEAWLSEKEELlssTDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDaeeiqerLE 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907202371 256 LICQRCNELRYLSDilvneirTKRVQLSRTFKVHRLLQQARQC---CDQGECLLASQGMDKfqTKEDAQKALQDVDNFlQ 332
Cdd:cd00176    83 ELNQRWEELRELAE-------ERRQRLEEALDLQQFFRDADDLeqwLEEKEAALASEDLGK--DLESVEELLKKHKEL-E 152

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*
gi 1907202371 333 MAMPFINYDIESLQYEFDVLLSPELKAQMQNIQLKLENIRSAFQN 377
Cdd:cd00176   153 EELEAHEPRLKSLNELAEELLEEGHPDADEEIEEKLEELNERWEE 197

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 1907202371 595 ITKYQlllkGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKH 674
Cdd:cd01227     2 ITGYD----GNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKN 71

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1907202371 675 CLKMEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 729
Cdd:cd01227    72 SLNTTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 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 1907202371  459 VLNELIQTERAYVRELFTVLLGYRSEMDNPQMFdlmppLLRNKKDVLFGNMAEIYEFHNnIFMSRLEDCS----DAPERV 534
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERIeewdDSVERI 74

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907202371  535 GPCFLERKDDFQMYAKYCQNKPRSELIWRKYSEC----AFFQECQRKLKH-RLGLDSYLLKPVQRITKYQLLLK 603
Cdd:smart00325  75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLK 148

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 1907202371  629 TKMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI 704
Cdd:smart00233   8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTL 80

                           90       100
                   ....*....|....*....|..
gi 1907202371  705 YIvQAPNVDVKMLWLKEIRKIL 726
Cdd:smart00233  81 LL-QAESEEEREKWVEALRKAI 101

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907202371 630 KMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI- 704
Cdd:pfam00169   9 KKGGGKKKSWKKRYFVLFDGSLLYYKDD-------KSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRTGERTGKr 81

                          90       100
                  ....*....|....*....|...
gi 1907202371 705 -YIVQAPNVDVKMLWLKEIRKIL 726
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 1907202371 595 ITKYQlllkGNINELGKMVLQGSFNVWLGHRKGATKmkDFARFKPMQRHLFLYEKAVMFCKRRFESGEGadryPSYSFKH 674
Cdd:cd01227     2 ITGYD----GNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKN 71

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1907202371 675 CLKMEDVGITEHVKGDNRKFEIRYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 729
Cdd:cd01227    72 SLNTTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 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 1907202371  459 VLNELIQTERAYVRELFTVLLGYRSEMDNPQMFdlmppLLRNKKDVLFGNMAEIYEFHNnIFMSRLEDCS----DAPERV 534
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERIeewdDSVERI 74

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907202371  535 GPCFLERKDDFQMYAKYCQNKPRSELIWRKYSEC----AFFQECQRKLKH-RLGLDSYLLKPVQRITKYQLLLK 603
Cdd:smart00325  75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLK 148

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 1907202371 605 NINELGKMVLQGSFNVWLGHRKGatkmkdfarfkpmQRHLFLYEKAVMFCK-RRFESGEGAdrypsYSFKHCLKMEDVGI 683
Cdd:cd13242    22 NLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKpKKTPGGKDV-----YIYKHSIKTSDIGL 83

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1907202371 684 TEHVKGDNRKFEI--RYSEKEEIYIVQAPNVDVKMLWLKEIRKILVQQ 729
Cdd:cd13242    84 TENVGDSGLKFEIwfRRRKARDTYILQATSPEIKQAWTSDIAKLLWKQ 131

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 1907202371 604 GNINELGKMVLQGSFNVWlghrKGATKMKDFARfkPMQRHLFLYEKAVMFCKRRFESGEGADrypSYSFKHCLKMEDVGI 683
Cdd:cd13239     7 APLQALGEPIRQGHFTVW----EEAPEVKTSSR--GHHRHVFLFKNCVVICKPKRDSRTDTV---TYVFKNKMKLSDIDV 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1907202371 684 TEHVKGDNRKFEIRYSEKEEI--YIVQAPNVDVKMLWLKEIRKIlvQQK 730
Cdd:cd13239    78 KDTVEGDDRSFGLWHEHRGSVrkYTLQARSAIIKSSWLKDLRDL--QQR 124

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 1907202371  629 TKMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI 704
Cdd:smart00233   8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTL 80

                           90       100
                   ....*....|....*....|..
gi 1907202371  705 YIvQAPNVDVKMLWLKEIRKIL 726
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 1907202371 604 GNINELGKMVLQGSFNVWlghrkgatkmkdFARFKPMQRHLFLYEKAVMFCKRRFESGEgadryPSYS-FKHCLKMEDVG 682
Cdd:cd13325     1 GNIHKLGRLLRHDWFTVT------------DGEGKAKERYLFLFKSRILITKVRRISED-----RSVFiLKDIIRLPEVN 63

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1907202371 683 ITEHvKGDNRKFEIRYS-EKEEIY--IVQAPNVDVKMLWLKEIRK 724
Cdd:cd13325    64 VKQH-PDDERTFELQPKlPAFGILpiDFKAHKDEIKDYWLNEIEE 107

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907202371 630 KMKDFARFKPMQRHLFLYEKAVMFCKRRfesgegaDRYPSYSFKHCLKMEDVGITEHVKGDNRK----FEIRYSEKEEI- 704
Cdd:pfam00169   9 KKGGGKKKSWKKRYFVLFDGSLLYYKDD-------KSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELRTGERTGKr 81

                          90       100
                  ....*....|....*....|...
gi 1907202371 705 -YIVQAPNVDVKMLWLKEIRKIL 726
Cdd:pfam00169  82 tYLLQAESEEERKDWIKAIQSAI 104

Spectrin repeats;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907202371  186 QDFQEAVTQVEFLLSQQREL---GDITGNLAQVKQRLKKLEILDDKSQELLTKARIVILRGHKLASNHHYALDLICQRCN 262
Cdd:smart00150   1 QQFLRDADELEAWLEEKEQLlasEDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERLE 80

                           90       100
                   ....*....|....*....|
gi 1907202371  263 ELRYLSDILVNEIRTKRVQL 282
Cdd:smart00150  81 ELNERWEELKELAEERRQKL 100