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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  573 RRHVMSELLDTERAYVEELLCVLEGYAAEMDNPLMahllsTGLHNKKDVLFGNMEEIYHFHnRIFLRELENYTDC----P 648
Cdd:cd00160      1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELL-----PLSPEEVELLFGNIEEIYEFH-RIFLKSLEERVEEwdksG 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  649 ELVGRCFLERMEDFQIYEKYCQNKPRSESLWRQC-SDCPFFQECQRKLD---HKLSLDSYLLKPVQRITKYQLLLKEMLK 724
Cdd:cd00160     75 PRIGDVFLKLAPFFKIYSEYCSNHPDALELLKKLkKFNKFFQEFLEKAEsecGRLKLESLLLKPVQRLTKYPLLLKELLK 154

                          170       180
                   ....*....|....*....|....*..
gi 1489866050  725 YS-RNCEGAEDLQEALSSILGILKAVN 750
Cdd:cd00160    155 HTpDGHEDREDLKKALEAIKEVASQVN 181

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRDPTTGKEGWVPASSLS 1053
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQWLVKNLSTRKEGWVPAANLQ 54

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  573 RRHVMSELLDTERAYVEELLCVLEGYAAEMDNPLMahllsTGLHNKKDVLFGNMEEIYHFHnRIFLRELENYTDC----P 648
Cdd:cd00160      1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELL-----PLSPEEVELLFGNIEEIYEFH-RIFLKSLEERVEEwdksG 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  649 ELVGRCFLERMEDFQIYEKYCQNKPRSESLWRQC-SDCPFFQECQRKLD---HKLSLDSYLLKPVQRITKYQLLLKEMLK 724
Cdd:cd00160     75 PRIGDVFLKLAPFFKIYSEYCSNHPDALELLKKLkKFNKFFQEFLEKAEsecGRLKLESLLLKPVQRLTKYPLLLKELLK 154

                          170       180
                   ....*....|....*....|....*..
gi 1489866050  725 YS-RNCEGAEDLQEALSSILGILKAVN 750
Cdd:cd00160    155 HTpDGHEDREDLKKALEAIKEVASQVN 181

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  576 VMSELLDTERAYVEELLCVLEGYAAEMDNPLMAHllstglHNKKDVLFGNMEEIYHFHNRIFLRELENYTDCPELVGRCF 655
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSES------EEEIKTIFSNIEEIYELHRQLLLEELLKEWISIQRIGDIF 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  656 LERMEDFQIYEKYCQNKPRSESLWRQCSD-----CPFFQECQ-RKLDHKLSLDSYLLKPVQRITKYQLLLKEMLKYSRNC 729
Cdd:pfam00621   75 LKFAPGFKVYSTYCSNYPKALKLLKKLLKknpkfRAFLEELEaNPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPD 154

                          170       180
                   ....*....|....*....|..
gi 1489866050  730 -EGAEDLQEALSSILGILKAVN 750
Cdd:pfam00621  155 hPDYEDLKKALEAIKEVAKQIN 176

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRDPTTGKEGWVPASSLS 1053
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQWLVKNLSTRKEGWVPAANLQ 54

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 1489866050  293 QLRHFEQGFREVKAILDAASQKIATfTDIGNSLAHVEHLLRDLASFEEKSGVAVERARALSLDGEQLIGNKHYAVDSIRP 372
Cdd:cd00176      1 KLQQFLRDADELEAWLSEKEELLSS-TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQE 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  373 KCQELRHLCDQFSAEIARRRGLLSKSLELHRRLETS---MKWCDEGIYLLASQPVDKcqSQDGAEAALQEIEKFLET--G 447
Cdd:cd00176     80 RLEELNQRWEELRELAEERRQRLEEALDLQQFFRDAddlEQWLEEKEAALASEDLGK--DLESVEELLKKHKELEEEleA 157

                          170       180       190
                   ....*....|....*....|....*....|...
gi 1489866050  448 AENKIQELNAIYKEYESILNQDLMEHVRKVFQK 480
Cdd:cd00176    158 HEPRLKSLNELAEELLEEGHPDADEEIEEKLEE 190

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 1489866050   771 LLMQGSFSVWTDHKRGHTKvkelarfkpmQRHLFLHEKAVLFCKKREENgegyekaPSYSYKQSLNMAAVGITENVKGDA 850
Cdd:smart00233    1 VIKEGWLYKKSGGGKKSWK----------KRYFVLFNSTLLYYKSKKDK-------KSYKPKGSIDLSGCTVREAPDPDS 63

                            90       100       110
                    ....*....|....*....|....*....|....*....
gi 1489866050   851 KK----FEIWYNAREeVYIVQAPTPEIKAAWVNEIRKVL 885
Cdd:smart00233   64 SKkphcFEIKTSDRK-TLLLQAESEEEREKWVEALRKAI 101

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

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....
gi 1489866050   997 VPGKYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRDPtTGKEGWVPAS 1050
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLG-RGKEGLFPSN 53

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 1489866050  292 LQLRHFEQGFREVKAILDAAsQKIATFTDIGNSLAHVEHLLRDLASFEEKSGVAVERARALSLDGEQLIGNKHYAVDSIR 371
Cdd:pfam00435    1 LLLQQFFRDADDLESWIEEK-EALLSSEDYGKDLESVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQ 79

                           90       100
                   ....*....|....*....|....
gi 1489866050  372 PKCQELRHLCDQFSAEIARRRGLL 395
Cdd:pfam00435   80 ERLEELNERWEQLLELAAERKQKL 103

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRdpTTGKEGWVPASSLSV 1054
Cdd:pfam07653    1 YGRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGE--TGGRVGLVPSTAVEE 53

Uncharacterized conserved protein YgiM, contains N-terminal SH3 domain, DUF1202 family [General function prediction only];

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1489866050 1016 RVRSGDVVELVQEGDEglWY-VRDPTtGKEGWVPAS--------------SLSVRLGPSGSAQ 1063
Cdd:COG3103     29 TLPKGEKVTVLGRSGG--WYkVRYSN-GKTGWVSSRyltvtpsarerlpdELNLRAGPSTSSE 88

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  573 RRHVMSELLDTERAYVEELLCVLEGYAAEMDNPLMahllsTGLHNKKDVLFGNMEEIYHFHnRIFLRELENYTDC----P 648
Cdd:cd00160      1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELL-----PLSPEEVELLFGNIEEIYEFH-RIFLKSLEERVEEwdksG 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  649 ELVGRCFLERMEDFQIYEKYCQNKPRSESLWRQC-SDCPFFQECQRKLD---HKLSLDSYLLKPVQRITKYQLLLKEMLK 724
Cdd:cd00160     75 PRIGDVFLKLAPFFKIYSEYCSNHPDALELLKKLkKFNKFFQEFLEKAEsecGRLKLESLLLKPVQRLTKYPLLLKELLK 154

                          170       180
                   ....*....|....*....|....*..
gi 1489866050  725 YS-RNCEGAEDLQEALSSILGILKAVN 750
Cdd:cd00160    155 HTpDGHEDREDLKKALEAIKEVASQVN 181

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  576 VMSELLDTERAYVEELLCVLEGYAAEMDNPLMAHllstglHNKKDVLFGNMEEIYHFHNRIFLRELENYTDCPELVGRCF 655
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSES------EEEIKTIFSNIEEIYELHRQLLLEELLKEWISIQRIGDIF 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  656 LERMEDFQIYEKYCQNKPRSESLWRQCSD-----CPFFQECQ-RKLDHKLSLDSYLLKPVQRITKYQLLLKEMLKYSRNC 729
Cdd:pfam00621   75 LKFAPGFKVYSTYCSNYPKALKLLKKLLKknpkfRAFLEELEaNPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPD 154

                          170       180
                   ....*....|....*....|..
gi 1489866050  730 -EGAEDLQEALSSILGILKAVN 750
Cdd:pfam00621  155 hPDYEDLKKALEAIKEVAKQIN 176

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 1489866050  750 NDSMHLIAITGYDGNLGDLGKLLMQGSFSVWTDHKRGhtkvkelarfkpmQRHLFLHEKAVLFCKKReengegyeKAPS- 828
Cdd:cd13242      8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKPK--------KTPGg 66

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  829 ---YSYKQSLNMAAVGITENVKGDAKKFEIWYNARE--EVYIVQAPTPEIKAAWVNEIRKVLTSqlQACR 893
Cdd:cd13242     67 kdvYIYKHSIKTSDIGLTENVGDSGLKFEIWFRRRKarDTYILQATSPEIKQAWTSDIAKLLWK--QAIR 134

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 1489866050  760 GYDGNLGDLGKLLMQGSFSVwtdhkrghTKVKELARFKPMQRHLFLHEKAVLFC----KKREENGegyekaPSYSYKQSL 835
Cdd:cd13241      6 GFDGKITAQGKLLLQGTLLV--------SEPSAGLLQKGKERRVFLFEQIIIFSeilgKKTQFSN------PGYIYKNHI 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1489866050  836 NMAAVGITENVKGDAKKFEIW---YNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQL 889
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 1489866050  758 ITGYDGNLGDLGKLLMQGSFSVWtDHKRGHTKVKElarfkpmqRHLFLHEKAVLFCKKrEENGEGYEKapsYSYKQSLNM 837
Cdd:cd13240      2 LEGCDEDLDSLGEVILQDSFQVW-DPKQLIRKGRE--------RHVFLFELCLVFSKE-VKDSNGKSK---YIYKSRLMT 68

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1489866050  838 AAVGITENVKGDAKKFEIW---YNAREEVYIVQAPTPEIKAAWVNEIRKVL 885
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 1489866050  758 ITGYDGNLGDLGKLLMQGSFSVWTDH------KRGHtkvkelarfkpmQRHLFLHEKAVLFCKKREENGEGYEkapSYSY 831
Cdd:cd13239      2 IENYPAPLQALGEPIRQGHFTVWEEApevktsSRGH------------HRHVFLFKNCVVICKPKRDSRTDTV---TYVF 66

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1489866050  832 KQSLNMAAVGITENVKGDAKKFEIWYNAREEV--YIVQAPTPEIKAAWVNEIRKV 884
Cdd:cd13239     67 KNKMKLSDIDVKDTVEGDDRSFGLWHEHRGSVrkYTLQARSAIIKSSWLKDLRDL 121

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. 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.

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                   ....*....|....*....|....*....|....*....|....*....|...
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRdpTTGKEGWVPASSL 1052
Cdd:cd11856      1 SYVAIADYEAQGDDEISLQEGEVVEVLEKNDSGWWYVR--KGDKEGWVPASYL 51

First Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the first SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRdpTTGKEGWVPASSL 1052
Cdd:cd12015      1 QYVVVADYKKQQPNEISLRAGDVVDVIEKNENGWWFVS--LEDEQGWVPATYL 51

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 1489866050  196 LAETELPNDVQSTSSVLCAHtekkdkakEDLRLALKEGHSVLESLRELQAEgsepsVNQDQLDNQATVQRLLAQLNETEA 275
Cdd:cd00176     23 LSSTDYGDDLESVEALLKKH--------EALEAELAAHEERVEALNELGEQ-----LIEEGHPDAEEIQERLEELNQRWE 89

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1489866050  276 AFDEFWAKHQQKLEQCLQLRHFEQGFREVKAILDAASQKIATfTDIGNSLAHVEHLLRDLASFEEKSGVAVERARALSLD 355
Cdd:cd00176     90 ELRELAEERRQRLEEALDLQQFFRDADDLEQWLEEKEAALAS-EDLGKDLESVEELLKKHKELEEELEAHEPRLKSLNEL 168

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*
gi 1489866050  356 GEQLIGNKHYAV-DSIRPKCQELRHLCDQFSAEIARRRGLLSKSL 399
Cdd:cd00176    169 AEELLEEGHPDAdEEIEEKLEELNERWEELLELAEERQKKLEEAL 213

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

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                   ....*....|....*....|....*....|....*....|....*....|...
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRdpTTGKEGWVPASSL 1052
Cdd:cd12074      1 QYVVVSNYEKQENSEISLQAGEVVDVIEKNESGWWFVS--TAEEQGWVPATYL 51

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1489866050 1001 YTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRDPTtgKEGWVPASSL 1052
Cdd:cd12021      2 YRAIADYEKSSKSEMALKTGDVVEVVEKSENGWWFCQLKA--KRGWVPASYL 51

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 1489866050  788 TKVKELARFKPMQRHLFLHEKAVLFCKKREENgegyekapSYSYKQSLNMAA-VGITENVKGDAK-KFEIWyNAREEVYI 865
Cdd:cd00821      6 LKRGGGGLKSWKKRWFVLFEGVLLYYKSKKDS--------SYKPKGSIPLSGiLEVEEVSPKERPhCFELV-TPDGRTYY 76

                           90
                   ....*....|....*.
gi 1489866050  866 VQAPTPEIKAAWVNEI 881
Cdd:cd00821     77 LQADSEEERQEWLKAL 92

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1489866050 1000 KYTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRdpTTGKEGWVPASSL 1052
Cdd:cd12075      2 QYVVVANYQKQESSEISLYVGQVVDIIEKNESGWWFVS--TADEQGWVPATCL 52

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1489866050 1001 YTVVADHEKGGPDALRVRSGDVVELVQEGDEGLWYVRDPTTGKEGWVPASSL 1052
Cdd:cd11858      2 YKALYDFAGSVANELSLKKDDIVYIVQKEDNGWWLAKKLDESKEGWVPAAYL 53

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 1489866050  292 LQLRHFEQGFREVKAILDAAsQKIATFTDIGNSLAHVEHLLRDLASFEEKSGVAVERARALSLDGEQLIGNKHYAVDSIR 371
Cdd:pfam00435    1 LLLQQFFRDADDLESWIEEK-EALLSSEDYGKDLESVQALLKKHKALEAELAAHQDRVEALNELAEKLIDEGHYASEEIQ 79

                           90       100
                   ....*....|....*....|....
gi 1489866050  372 PKCQELRHLCDQFSAEIARRRGLL 395
Cdd:pfam00435   80 ERLEELNERWEQLLELAAERKQKL 103