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 346986245  773 LLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPSVISLQKLIAREVANEERGMFLISASSAGPEMY 852
Cdd:cd14680     1 LLHEGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPPVICLQKLIVREVANEERGMFLISASSAGPEMY 80

                          90       100
                  ....*....|....*....|.
gi 346986245  853 EIHTNSKEERNTWMRRIQQAV 873
Cdd:cd14680    81 EIHTSSKEERNNWMRLIQEAV 101

protein kinase C conserved region 1 (C1 domain) found in 190 kDa guanine nucleotide exchange factor (p190RhoGEF) and similar proteins; p190RhoGEF, also called Rho guanine nucleotide exchange factor (RGNEF), Rho guanine nucleotide exchange factor 28 (ARHGEF28), or RIP2, is a brain-enriched, RhoA-specific guanine nucleotide exchange factor that regulates signaling pathways downstream of integrins and growth factor receptors. It is involved in axonal branching, synapse formation and dendritic morphogenesis, as well as in focal adhesion formation, cell motility and B-lymphocytes activation. In addition to the Dbl homology (DH)-PH domain, p190RhoGEF contains an N-terminal C1 (Protein kinase C conserved region 1) domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 346986245  332 DKEKLTRHQFVPGTFSGVLQCLVCDKTLLGKESFQCSNCNGNVHKVCKDAAPPCTKKFQDK 392
Cdd:cd20876     1 KEKQSNGHQFVTGSFSGPTLCVVCDKPVTGKELLQCSNCTVNVHKGCKESAPPCTKKLQDK 61

Rho guanine nucleotide exchange factor Pleckstrin homology domain; p190RhoGEF (also called RIP2 or ARHGEF28) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. In addition to the Dbl homology (DH)-PH domain, p190RhoGEF contains an N-terminal C1 (Protein kinase C conserved region 1) domain. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. 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 346986245  773 LLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPSVISLQKLIAREVANEERGMFLISASSAGPEMY 852
Cdd:cd14680     1 LLHEGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPPVICLQKLIVREVANEERGMFLISASSAGPEMY 80

                          90       100
                  ....*....|....*....|.
gi 346986245  853 EIHTNSKEERNTWMRRIQQAV 873
Cdd:cd14680    81 EIHTSSKEERNNWMRLIQEAV 101

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 346986245  536 RQDVIFELMQTELHHIQTLFIMSEIFRKGMKEELQ-LDHSTVDKIFPCLDELLEIHKHFFCSMKERRQEScvgndrNFII 614
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEW------DKSG 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  615 GRIGDILVQQFSeenankMKKIYGEFCSHHKEAVSLFKELQQ-NKKFQNFIKLRNSNllARRRGIPECILLVTQRITKYP 693
Cdd:cd00160    75 PRIGDVFLKLAP------FFKIYSEYCSNHPDALELLKKLKKfNKFFQEFLEKAESE--CGRLKLESLLLKPVQRLTKYP 146

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 346986245  694 VLVERILQYTKESTEEQRDLCKALCLIKDMIAAVD 728
Cdd:cd00160   147 LLLKELLKHTPDGHEDREDLKKALEAIKEVASQVN 181

PH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245   755 LKNGHVFRKQALmsKERTLLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAA-------VDQK--PSVISLQ 825
Cdd:pfam17838    1 HPLGEEFKKLDL--TTRKLIHEGPLTWRNSKGKLVEVHALLLEDILVLLQEKDQKLVLAClstgsenVDQKtqSPIISLK 78

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 346986245   826 KLIAREVANEERGMFLISASSAGPEMYEIHTNSKEERNTWMRRIQQAVE 874
Cdd:pfam17838   79 KLIVREVATDKKAFFLISTSPSDPQMYELHASTKSERNTWTKLIQDAIE 127

Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains); Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|
gi 346986245    339 HQFVPGTFSGVLQCLVCDKTLLG--KESFQCSNCNGNVHKVCKDAAP-PC 385
Cdd:smart00109    1 HKHVFRTFTKPTFCCVCRKSIWGsfKQGLRCSECKVKCHKKCADKVPkAC 50

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  503 SDLSGDAQEFEAESWSLVVDPSFCSRQEKDVIQRQDVIFELMQTELHHIQTLFIMSEIFRKGMkEELQLDHSTVDKIF-- 580
Cdd:COG5422   452 SSLALDKFDEEKNLWTLSVPKEVWESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPL-EESNIIPENARRNFik 530

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  581 PCLDELLEIHKHFFCSMKERRQESCVGNdrnfIIGRIGDILVQQFSeenankmkkIYGEFCSHHKE---AVSLF-KELQQ 656
Cdd:COG5422   531 HVFANINEIYAVNSKLLKALTNRQCLSP----IVNGIADIFLDYVP---------KFEPFIKYGASqpyAKYEFeREKSV 597

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  657 NKKFQNFIKLRNSNLLARRRGIPECILLVTQRITKYPVLVERILQYTKESTEEQRDLCKALCLIKDMIAAVDLKVSEYEK 736
Cdd:COG5422   598 NPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAEN 677

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 346986245  737 -------KQKWL---EILNKIENKTYTKLKNGHVFRKQALMSKERTLLYD 776
Cdd:COG5422   678 rgdlfhlNQQLLfkpEYVNLGLNDEYRKIIFKGVLKRKAKSKTDGSLRGD 727

Domain of unknown function (DUF4659); This family of proteins is found in eukaryotes. Proteins in this family are typically between 427 and 674 amino acids in length. There are two completely conserved residues (D and I) that may be functionally important.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  1110 QEKSRSLEKQREELADTHKLQLQfqQDQHRWLRRCDQQQ----REQEARASRLQ----ERERECRAQEELLLRSRGELDQ 1181
Cdd:pfam15558   35 EELRRRDQKRQETLERERRLLLQ--QSQEQWQAEKEQRKarlgREERRRADRREkqviEKESRWREQAEDQENQRQEKLE 112

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 346986245  1182 QLQDYQQSLERLREgQRLVERERER--MRAQQSLLRHWK-----HGRQssLPAAFSPgaLEVMELNRSETLRHE 1248
Cdd:pfam15558  113 RARQEAEQRKQCQE-QRLKEKEEELqaLREQNSLQLQERleeacHKRQ--LKEREEQ--KKVQENNLSELLNHQ 181

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
                    ....*....|....*....|....*....|....*....|....*....|....*..
gi 346986245    821 VISLQKLIAREVAN----EERGMFLISasSAGPEMYEIHTNSKEERNTWMRRIQQAV 873
Cdd:smart00233   47 SIDLSGCTVREAPDpdssKKPHCFEIK--TSDRKTLLLQAESEEEREKWVEALRKAI 101

Rho guanine nucleotide exchange factor Pleckstrin homology domain; p190RhoGEF (also called RIP2 or ARHGEF28) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. In addition to the Dbl homology (DH)-PH domain, p190RhoGEF contains an N-terminal C1 (Protein kinase C conserved region 1) domain. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. 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 346986245  773 LLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPSVISLQKLIAREVANEERGMFLISASSAGPEMY 852
Cdd:cd14680     1 LLHEGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPPVICLQKLIVREVANEERGMFLISASSAGPEMY 80

                          90       100
                  ....*....|....*....|.
gi 346986245  853 EIHTNSKEERNTWMRRIQQAV 873
Cdd:cd14680    81 EIHTSSKEERNNWMRLIQEAV 101

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 346986245    539 VIFELMQTELHHIQTLFIMSEIFRKGMKEELQ-LDHSTVDKIFPCLDELLEIHKHFFCSMKERRQESCVGNDRnfiigrI 617
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKlLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDSVER------I 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245    618 GDILVQQfseenaNKMKKIYGEFCSHHKEAVSLFKELQQNKKFQNFIKLRNSNLLARRRGIPECILLVTQRITKYPVLVE 697
Cdd:smart00325   75 GDVFLKL------EEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLK 148

                           170       180       190
                    ....*....|....*....|....*....|.
gi 346986245    698 RILQYTKESTEEQRDLCKALCLIKDMIAAVD 728
Cdd:smart00325  149 ELLKHTPEDHEDREDLKKALKAIKELANQVN 179

Rho guanine nucleotide exchange factor 2 Pleckstrin homology (PH) domain; ARHGEF2, also called GEF-H1, acts as guanine nucleotide exchange factor (GEF) for RhoA GTPases. It is thought to play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. ARHGEF2 contains a C1 domain followed by Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. 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 346986245  771 RTLLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDqKPSVISLQKLIAREVANEERGMFLISAssAGPE 850
Cdd:cd13393     2 RKLIHDGCLLWKTASGRFKDVQVLLMTDVLVFLQEKDQKYIFPTLD-KPAVISLQNLIVRDIANQEKGMFLISA--APPE 78

                          90       100       110
                  ....*....|....*....|....*....|
gi 346986245  851 MYEIHTNSKEERNTWMRRIQQAVESCPEEE 880
Cdd:cd13393    79 MYEVHAASRDDRNTWMRLIQQTVKTCPSRE 108

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 346986245   539 VIFELMQTELHHIQTLFIMSEIFRKGMKEELQLDHSTVDKIFPCLDELLEIHKHFFcsMKERRQEscvgndrNFIIGRIG 618
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKE-------WISIQRIG 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245   619 DILVQQFSeenankMKKIYGEFCSHHKEAVSLFKELQQ-NKKFQNFIKLRNSNLLARRRGIPECILLVTQRITKYPVLVE 697
Cdd:pfam00621   72 DIFLKFAP------GFKVYSTYCSNYPKALKLLKKLLKkNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLK 145

                          170       180       190
                   ....*....|....*....|....*....|.
gi 346986245   698 RILQYTKESTEEQRDLCKALCLIKDMIAAVD 728
Cdd:pfam00621  146 ELLKHTPPDHPDYEDLKKALEAIKEVAKQIN 176

protein kinase C conserved region 1 (C1 domain) found in 190 kDa guanine nucleotide exchange factor (p190RhoGEF) and similar proteins; p190RhoGEF, also called Rho guanine nucleotide exchange factor (RGNEF), Rho guanine nucleotide exchange factor 28 (ARHGEF28), or RIP2, is a brain-enriched, RhoA-specific guanine nucleotide exchange factor that regulates signaling pathways downstream of integrins and growth factor receptors. It is involved in axonal branching, synapse formation and dendritic morphogenesis, as well as in focal adhesion formation, cell motility and B-lymphocytes activation. In addition to the Dbl homology (DH)-PH domain, p190RhoGEF contains an N-terminal C1 (Protein kinase C conserved region 1) domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 346986245  332 DKEKLTRHQFVPGTFSGVLQCLVCDKTLLGKESFQCSNCNGNVHKVCKDAAPPCTKKFQDK 392
Cdd:cd20876     1 KEKQSNGHQFVTGSFSGPTLCVVCDKPVTGKELLQCSNCTVNVHKGCKESAPPCTKKLQDK 61

rho guanine nucleotide exchange factor; RhoGEFs belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. The members here all contain Dbl homology (DH)-PH domains. In addition some members contain N-terminal C1 (Protein kinase C conserved region 1) domains, PDZ (also called DHR/Dlg homologous regions) domains, ANK (ankyrin) domains, and RGS (Regulator of G-protein signalling) domains or C-terminal ATP-synthase B subunit. The DH-PH domains bind and catalyze the exchange of GDP for GTP on RhoA. RhoGEF2/Rho guanine nucleotide exchange factor 2, p114RhoGEF/p114 Rho guanine nucleotide exchange factor, p115RhoGEF, p190RhoGEF, PRG/PDZ Rho guanine nucleotide exchange factor, RhoGEF 11, RhoGEF 12, RhoGEF 18, AKAP13/A-kinase anchoring protein 13, and LARG/Leukemia-associated Rho guanine nucleotide exchange factor are included in this CD. 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 346986245  773 LLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIFAAVDQKPSVISLQKLIAREVANEERGMFLISASSAG-PEM 851
Cdd:cd15789     1 LKFEGTAWLKQARGKTKDVLVVVLTDVLFFLQEKDQKYVFVSPDNKAGVVSLQKLLVREKAGQEKRMFLISASPDGmPEM 80

                          90       100
                  ....*....|....*....|..
gi 346986245  852 YEIHTNSKEERNTWMRRIQQAV 873
Cdd:cd15789    81 YELKVQKPKDKNTWIQTIRQAV 102

protein kinase C conserved region 1 (C1 domain) found in A-kinase anchor protein 13 (AKAP-13) and similar proteins; AKAP-13, also called AKAP-Lbc, breast cancer nuclear receptor-binding auxiliary protein (Brx-1), guanine nucleotide exchange factor Lbc, human thyroid-anchoring protein 31, lymphoid blast crisis oncogene (LBC oncogene), non-oncogenic Rho GTPase-specific GTP exchange factor, protein kinase A-anchoring protein 13 (PRKA13), or p47, is a scaffold protein that plays an important role in assembling signaling complexes downstream of several types of G protein-coupled receptors (GPCRs). It activates RhoA in response to GPCR signaling via its function as a Rho guanine nucleotide exchange factor. It may also activate other Rho family members. AKAP-13 plays a role in cell growth, cell development and actin fiber formation. Its Rho-GEF activity is regulated by protein kinase A (PKA), through binding and phosphorylation. Alternative splicing of this gene in humans has at least 3 transcript variants encoding different isoforms (i.e. proto-/onco-Lymphoid blast crisis, Lbc and breast cancer nuclear receptor-binding auxiliary protein, and Brx) that contain a C1 domain followed by a dbl oncogene homology (DH) domain and a PH domain which are required for full transforming activity. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 346986245  332 DKEKLTRHQFVPGTFSGVLQCLVCDKTLLGKESFQCSNCNGNVHKVCKDAAPPCTK 387
Cdd:cd20878     1 DKKTLNGHVFSPVSSVGPTQCYHCSKPLNTKDAFLCANCNVQVHKGCRESLPVCAK 56

PDZ Rho guanine nucleotide exchange factor Pleckstrin homology (PH) domain; PRG (also called RhoGEF11) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. RhoGEFs activate Rho GTPases regulating cytoskeletal structure, gene transcription, and cell migration. PRG contains an N-terminal PDZ domain, a regulators of G-protein signaling-like (RGSL) domain, a linker region, and a C-terminal Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. As is the case in p115-RhoGEF, it is thought that the PRG activated by relieving autoinhibition caused by the linker region. 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 346986245  771 RTLLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIF--------AAVDQKPS---VISLQKLIAREVANEERGM 839
Cdd:cd13391    26 RRMIHEGPLTWRISKDKTLDLHVLLLEDLLVLLQKQDEKLVLkchsktavGSSDSKQTfspVLKLNSVLIRSVATDKRAL 105

                          90       100       110
                  ....*....|....*....|....*....|....
gi 346986245  840 FLISASSAGPEMYEIHTNSKEERNTWMRRIQQAV 873
Cdd:cd13391   106 FIICTSKLGPQIYELVALTSSEKNTWMELLEEAV 139

protein kinase C conserved region 1 (C1 domain) found in Rho guanine nucleotide exchange factor 2 (ARHGEF2) and similar proteins; ARHGEF2, also called guanine nucleotide exchange factor H1 (GEF-H1), microtubule-regulated Rho-GEF, or proliferating cell nucleolar antigen p40, acts as guanine nucleotide exchange factor (GEF) that activates Rho-GTPases by promoting the exchange of GDP for GTP. It is thought to play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. ARHGEF2 may be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. It contains a C1 domain followed by Dbl-homology (DH) and pleckstrin-homology (PH) domains which bind and catalyze the exchange of GDP for GTP on RhoA. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 346986245  339 HQFVPGTFSGVLQCLVCDKTLLGKESFQCSNCNGNVHKVCKDAAPPCTK 387
Cdd:cd20877     6 HLFTTITVSGTTMCSACNKSITAKEALICPTCNVTIHNRCKDTLPNCTK 54

Leukemia-associated Rho guanine nucleotide exchange factor Pleckstrin homology (PH) domain; LARG (also called RhoGEF12) belongs to regulator of G-protein signaling (RGS) domain-containing RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. RhoGEFs activate Rho GTPases regulating cytoskeletal structure, gene transcription, and cell migration. LARG contains a N-terminal extension, followed by Dbl homology (DH)-PH domains which bind and catalyze the exchange of GDP for GTP on RhoA in addition to a RGS domain. The active site of RhoA adopts two distinct GDP-excluding conformations among the four unique complexes in the asymmetric unit. The LARG PH domain also contains a potential protein-docking site. LARG forms a homotetramer via its DH domains. 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 346986245  770 ERTLLYDGLVYWKTATGRFKDILALLLTDVLLFLQEKDQKYIF--------AAVDQKPS---VISLQKLIAREVANEERG 838
Cdd:cd13390    23 KRKMIHEGPLTWKVNRDKTIDLYTLLLEDILVLLQKQDDRLVLrchskilaSTADSKHTfspVIKLNTVLVRQVATDNKA 102

                          90       100       110
                  ....*....|....*....|....*....|...
gi 346986245  839 MFLISASSAGPEMYEIHTNSKEERNTWMRRIQQ 871
Cdd:cd13390   103 FFVISMSENGAQIYELVAQTVSEKTVWQDLITR 135

protein kinase C conserved region 1 (C1 domain) found in VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and as scaffold proteins, and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 346986245  337 TRHQFVPGTFSGVLQCLVCDKTLLG--KESFQCSNCNGNVHKVCKDAAPPC 385
Cdd:cd20810     1 TGHSFELTTFKEPTTCSVCKKLLKGlfFQGYKCSVCGAAVHKECIAKVKRC 51

protein kinase C conserved region 1 (C1 domain) found in Drosophila melanogaster GM13116p and similar proteins; This group contains uncharacterized proteins including Drosophila melanogaster GM13116p and Caenorhabditis elegans hypothetical protein R11G1.4, both of which contain C2 (a calcium-binding domain) and C1 domains. This model describes the C1 domain, a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 346986245  339 HQFVPGTFSGVLQCLVCDKTL---LGKESFQCSNCNGNVHKVC 378
Cdd:cd20831     6 HTFVATHFKGGPSCAVCNKLIpgrFGKQGYQCRDCGLICHKRC 48

protein kinase C conserved region 1 (C1 domain) found in myotonic dystrophy kinase-related Cdc42-binding kinase gamma (MRCK gamma) and similar proteins; MRCK gamma (MRCKG), also called Cdc42-binding protein kinase gamma, DMPK-like gamma, myotonic dystrophy protein kinase-like gamma, or myotonic dystrophy protein kinase-like alpha, is a serine/threonine-protein kinase expressed in heart and skeletal muscles. It may act as a downstream effector of Cdc42 in cytoskeletal reorganization and contributes to the actomyosin contractility required for cell invasion, through the regulation of MYPT1 and thus MLC2 phosphorylation. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 346986245  339 HQFVPGTFSGVLQCLVCDKTLLG--KESFQCSNCNGNVHKVCKDAAPPC 385
Cdd:cd20866     1 HTFKPKTFTSPTKCLRCTSLMVGlvRQGLACEACNYVCHVSCAEGAPIC 49

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  503 SDLSGDAQEFEAESWSLVVDPSFCSRQEKDVIQRQDVIFELMQTELHHIQTLFIMSEIFRKGMkEELQLDHSTVDKIF-- 580
Cdd:COG5422   452 SSLALDKFDEEKNLWTLSVPKEVWESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPL-EESNIIPENARRNFik 530

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  581 PCLDELLEIHKHFFCSMKERRQESCVGNdrnfIIGRIGDILVQQFSeenankmkkIYGEFCSHHKE---AVSLF-KELQQ 656
Cdd:COG5422   531 HVFANINEIYAVNSKLLKALTNRQCLSP----IVNGIADIFLDYVP---------KFEPFIKYGASqpyAKYEFeREKSV 597

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245  657 NKKFQNFIKLRNSNLLARRRGIPECILLVTQRITKYPVLVERILQYTKESTEEQRDLCKALCLIKDMIAAVDLKVSEYEK 736
Cdd:COG5422   598 NPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAEN 677

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 346986245  737 -------KQKWL---EILNKIENKTYTKLKNGHVFRKQALMSKERTLLYD 776
Cdd:COG5422   678 rgdlfhlNQQLLfkpEYVNLGLNDEYRKIIFKGVLKRKAKSKTDGSLRGD 727

Uncharacterized conserved protein, contains a C-terminal ATPase domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1060 QAIQNLTRLLYS--------LQAALTIQDS---HIEIHRLVL---QQRESLAPGPAfrgspfqDQEKSRSLEKQREELaD 1125
Cdd:COG4913   204 KPIGDLDDFVREymleepdtFEAADALVEHfddLERAHEALEdarEQIELLEPIRE-------LAERYAAARERLAEL-E 275

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1126 THKLQLQFQQDQHRW------LRRCDQQQREQEARASRLQERERECRAQEELLLRSRGELDQQLqdyqqsLERLREGQRL 1199
Cdd:COG4913   276 YLRAALRLWFAQRRLelleaeLEELRAELARLEAELERLEARLDALREELDELEAQIRGNGGDR------LEQLEREIER 349

                         170
                  ....*....|....*...
gi 346986245 1200 VERERERMRAQQSLLRHW 1217
Cdd:COG4913   350 LERELEERERRRARLEAL 367

protein kinase C conserved region 1 (C1 domain) found in male germ cell RacGap (MgcRacGAP) and similar proteins; MgcRacGAP, also called Rac GTPase-activating protein 1 (RACGAP1) or protein CYK4, plays an important dual role in cytokinesis: i) it is part of centralspindlin-complex, together with the mitotic kinesin MKLP1, which is critical for the structure of the central spindle by promoting microtuble bundling; and ii) after phosphorylation by aurora B, MgcRacGAP becomes an effective regulator of RhoA and plays an important role in the assembly of the contractile ring and the initiation of cytokinesis. MgcRacGAP-like proteins contain an N-terminal C1 domain, and a C-terminal RhoGAP domain. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 346986245  339 HQFVPGT--FSGVlqCLVCDKTL-LGKESFQCSNCNGNVHKVCKDAAP-PC 385
Cdd:cd20821     3 HRFVSKTviKPET--CVVCGKRIkFGKKALKCKDCRVVCHPDCKDKLPlPC 51

first protein kinase C conserved region 1 (C1 domain) found in Saccharomyces cerevisiae protein kinase C-like 1 (ScPKC1) and similar proteins; ScPKC1 is required for cell growth and for the G2 to M transition of the cell division cycle. It mediates a protein kinase cascade, activating BCK1 which itself activates MKK1/MKK2. The family also includes Schizosaccharomyces pombe PKC1 and PKC2, which are involved in the control of cell shape and act as targets of the inhibitor staurosporine. Members of this family contain two copies of the C1 domain. This model corresponds to the first one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 346986245  339 HQFVPGTFSGVLQCLVCDKtLLGKESFQCSNCNGNVHKVC 378
Cdd:cd20822     3 HKFVQKQFYQIMRCAVCGE-FLVNAGYQCEDCKYTCHKKC 41

exonuclease subunit SbcC; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1087 RLVLQQRESLAPGPAFrgspfQDQEKSRSLEKQREELADTHKLQL---QFQQDQHRWLRRCDQQQREQEARASRLQE-RE 1162
Cdd:PRK10246  197 RTELEKLQAQASGVAL-----LTPEQVQSLTASLQVLTDEEKQLLtaqQQQQQSLNWLTRLDELQQEASRRQQALQQaLA 271

                  ....*....
gi 346986245 1163 RECRAQEEL 1171
Cdd:PRK10246  272 AEEKAQPQL 280

Chromosome condensin MukBEF, ATPase and DNA-binding subunit MukB [Cell cycle control, cell division, chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1063 QNLTRLLYSLQAALTIQDSHIEIHRLVLQQRESLAPGpafrgspfqdQEKSRSLEKQREELADTHKLQLQFQQ-----DQ 1137
Cdd:COG3096   451 QQATEEVLELEQKLSVADAARRQFEKAYELVCKIAGE----------VERSQAWQTARELLRRYRSQQALAQRlqqlrAQ 520

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1138 HRWLRRCDQQQREQEARASRLQERERECRAQEELLLRSRGELDQQLQDYQQSLERLREGQRLVERERERMRAQQSLLR-- 1215
Cdd:COG3096   521 LAELEQRLRQQQNAERLLEEFCQRIGQQLDAAEELEELLAELEAQLEELEEQAAEAVEQRSELRQQLEQLRARIKELAar 600

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 346986245 1216 --HW--------KHGRQSSLPAAFSPGALEVMElnrsETLRHE 1248
Cdd:COG3096   601 apAWlaaqdaleRLREQSGEALADSQEVTAAMQ----QLLERE 639

first protein kinase C conserved region 1 (C1 domain) found in classical (or conventional) protein kinase C (cPKC), novel protein kinase C (nPKC), and similar proteins; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domains. PKCs undergo three phosphorylations in order to take mature forms. In addition, cPKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. nPKCs are calcium-independent, but require DAG and PS for activity, while atypical PKCs (aPKCs) only require PS. PKCs phosphorylate and modify the activities of a wide variety of cellular proteins including receptors, enzymes, cytoskeletal proteins, transcription factors, and other kinases. They play a central role in signal transduction pathways that regulate cell migration and polarity, proliferation, differentiation, and apoptosis. This family includes classical PKCs (cPKCs) and novel PKCs (nPKCs). There are four cPKC isoforms (named alpha, betaI, betaII, and gamma) and four nPKC isoforms (delta, epsilon, eta, and theta). Members of this family contain two copies of the C1 domain. This model corresponds to the first one. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 346986245  339 HQFVPGTFSGVLQCLVCDKTL--LGKESFQCSNCNGNVHKVC-KDAAPPCTK 387
Cdd:cd20792     2 HKFVATFFKQPTFCSHCKDFIwgLGKQGYQCQVCRFVVHKRChEYVVFKCPG 53

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1026 DAGTQGVGTDLAVSDAGEKVEYRSFPGSLQSEIIQAIQNLTRLLyslqAALTIQDSHIEIHRLVLQQRESLAPGPA-FRG 1104
Cdd:COG1196   590 AALARGAIGAAVDLVASDLREADARYYVLGDTLLGRTLVAARLE----AALRRAVTLAGRLREVTLEGEGGSAGGSlTGG 665

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 346986245 1105 SPFQDQEKSRSLEKQREELADTHKLQLQFQQDQHRWLRRCDQQQREQEARASRLQERERECRAQEELLLRSR-------- 1176
Cdd:COG1196   666 SRRELLAALLEAEAELEELAERLAEEELELEEALLAEEEEERELAEAEEERLEEELEEEALEEQLEAEREELleelleee 745