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 694849578 1035 RLDATSLERTSNPLAAEFKSLDLTSRRMIHEGPLTWRISKDKTVDLHVLLLEDLLVLLQKQDEKLVLKCHSKTALGSSDN 1114
Cdd:cd13391     1 RLDATALERASNPLAAEFKNLDLTTRRMIHEGPLTWRISKDKTLDLHVLLLEDLLVLLQKQDEKLVLKCHSKTAVGSSDS 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 694849578 1115 KQTFSPVLKLNSVLIRSVATDKRALFIICTSELGPQIYELVALTSSEKNTWMELLEEAVQSA 1176
Cdd:cd13391    81 KQTFSPVLKLNSVLIRSVATDKRALFIICTSKLGPQIYELVALTSSEKNTWMELLEEAVRNA 142

PDZ domain of ARHGEF11, ARHGEF12, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of ARHGEF11, ARHGEF12, and related domains. This subfamily includes the GEFs (guanine exchange factors) ARHGEF11 (Rho guanine nucleotide exchange factor 11, known as PDZ-RhoGEF) and ARHGEF12 (Rho guanine nucleotide exchange factor 12, also known as leukemia-associated RhoGEF). GEFs activate Rho GTPases by promoting GTP binding. ARHGEF11/12 are regulators of G protein signaling (RGS) domain-containing GEFs; the RGS domain mediates their binding to and activation of Galpha (and Gq also in the case of ARHGEF12), in response to G-protein coupled receptor activation. ARHGEF11 and 12 are involved in serum-signaling, and regulate Yes-Associated Protein (YAP1)-dependent transcription. The ARHGEF12 PDZ domain binds plexin-B1 and the receptor tyrosine kinase insulin-like growth factor receptor (IGF-R1) beta-subunit. ARHGEF12 also interacts with glutamate receptor delta-1(GluD1), a postsynaptic organizer of inhibitory synapses in cortical pyramidal neurons. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This ARHGEF11-12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 694849578   96 QRCVVIQKDQHGFGFTVSGDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIKSGAYVALTLL 171
Cdd:cd23069     1 QRCVVIQRDENGYGLTVSGDNPVFVQSVKEGGAAYRAGVQEGDRIIKVNGTLVTHSNHLEVVKLIKSGSYVALTLL 76

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 694849578 1035 RLDATSLERTSNPLAAEFKSLDLTSRRMIHEGPLTWRISKDKTVDLHVLLLEDLLVLLQKQDEKLVLKCHSKTALGSSDN 1114
Cdd:cd13391     1 RLDATALERASNPLAAEFKNLDLTTRRMIHEGPLTWRISKDKTLDLHVLLLEDLLVLLQKQDEKLVLKCHSKTAVGSSDS 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 694849578 1115 KQTFSPVLKLNSVLIRSVATDKRALFIICTSELGPQIYELVALTSSEKNTWMELLEEAVQSA 1176
Cdd:cd13391    81 KQTFSPVLKLNSVLIRSVATDKRALFIICTSKLGPQIYELVALTSSEKNTWMELLEEAVRNA 142

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 694849578  831 RQEVINELFATEGSHLRILRVLDLLFYQRMKKESL-LSREELALLFPNLPDLIEIHNSLSESMKKLREEGPiikEIGDLM 909
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWD---KSGPRI 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  910 LSRFDGLAkeEIQQVAADFCSYQSIALELIKTKQRKETRFQIFMQEAESnpQCRRLQLKDLIISEMQRLTKYPLLLENII 989
Cdd:cd00160    78 GDVFLKLA--PFFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAES--ECGRLKLESLLLKPVQRLTKYPLLLKELL 153

                         170       180
                  ....*....|....*....|....*...
gi 694849578  990 KHTEAGTSEHDKLCRARDQCRDILKYVN 1017
Cdd:cd00160   154 KHTPDGHEDREDLKKALEAIKEVASQVN 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 694849578   834 VINELFATEGSHLRILRVLDLLFYQRMKKESLLSREELALLFPNLPDLIEIHNSLSesMKKLREEGPIIKEIGDLMLSRF 913
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWISIQRIGDIFLKFA 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578   914 DGLakeeiqQVAADFCSYQSIALELIKTKQRKETRFQIFMQEAESNPQCRRLQLKDLIISEMQRLTKYPLLLENIIKHTE 993
Cdd:pfam00621   79 PGF------KVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTP 152

                          170       180
                   ....*....|....*....|....
gi 694849578   994 AGTSEHDKLCRARDQCRDILKYVN 1017
Cdd:pfam00621  153 PDHPDYEDLKKALEAIKEVAKQIN 176

PDZ domain of ARHGEF11, ARHGEF12, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of ARHGEF11, ARHGEF12, and related domains. This subfamily includes the GEFs (guanine exchange factors) ARHGEF11 (Rho guanine nucleotide exchange factor 11, known as PDZ-RhoGEF) and ARHGEF12 (Rho guanine nucleotide exchange factor 12, also known as leukemia-associated RhoGEF). GEFs activate Rho GTPases by promoting GTP binding. ARHGEF11/12 are regulators of G protein signaling (RGS) domain-containing GEFs; the RGS domain mediates their binding to and activation of Galpha (and Gq also in the case of ARHGEF12), in response to G-protein coupled receptor activation. ARHGEF11 and 12 are involved in serum-signaling, and regulate Yes-Associated Protein (YAP1)-dependent transcription. The ARHGEF12 PDZ domain binds plexin-B1 and the receptor tyrosine kinase insulin-like growth factor receptor (IGF-R1) beta-subunit. ARHGEF12 also interacts with glutamate receptor delta-1(GluD1), a postsynaptic organizer of inhibitory synapses in cortical pyramidal neurons. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This ARHGEF11-12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 694849578   96 QRCVVIQKDQHGFGFTVSGDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIKSGAYVALTLL 171
Cdd:cd23069     1 QRCVVIQRDENGYGLTVSGDNPVFVQSVKEGGAAYRAGVQEGDRIIKVNGTLVTHSNHLEVVKLIKSGSYVALTLL 76

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  792 LLEDEQGQLSD-----LEPELDSQN-WQHTVSRELVANLPQKEIDRQEVINELFATEGSHLRILRVLDLLFYQRMKKESL 865
Cdd:COG5422   440 LHLKLMGGLKRnsslaLDKFDEEKNlWTLSVPKEVWESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNI 519

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  866 LS----REELALLFPNLPDLIEIHNSLSESMKKLREEGPIIKEIGDLMLsRFDGLAKEEIQQVAAdfcsyQSIALELIKT 941
Cdd:COG5422   520 IPenarRNFIKHVFANINEIYAVNSKLLKALTNRQCLSPIVNGIADIFL-DYVPKFEPFIKYGAS-----QPYAKYEFER 593

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  942 KQRKETRFQIFMQEAESNPQCRRLQLKDLIISEMQRLTKYPLLLENIIKHTEAGTSEHDKLCRARDQCRDILKYVNEAVK 1021
Cdd:COG5422   594 EKSVNPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESG 673

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|
gi 694849578 1022 RAENRHRLEGYQKRLdatslerTSNPLAAEFKSLDlTSRRMIHEGPLTWR 1071
Cdd:COG5422   674 KAENRGDLFHLNQQL-------LFKPEYVNLGLND-EYRKIIFKGVLKRK 715

C-terminal processing protease CtpA/Prc, contains a PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 694849578  107 GFGFTVS-GDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLI--KSGAYVALTLL 171
Cdd:COG0793    61 GLGAELGeEDGKVVVVSVIPGSPAEKAGIKPGDIILAIDGKSVAGLTLDDAVKLLrgKAGTKVTLTIK 128

periplasmic serine protease, Do/DeqQ family; This family consists of a set proteins various designated DegP, heat shock protein HtrA, and protease DO. The ortholog in Pseudomonas aeruginosa is designated MucD and is found in an operon that controls mucoid phenotype. This family also includes the DegQ (HhoA) paralog in E. coli which can rescue a DegP mutant, but not the smaller DegS paralog, which cannot. Members of this family are located in the periplasm and have separable functions as both protease and chaperone. Members have a trypsin domain and two copies of a PDZ domain. This protein protects bacteria from thermal and other stresses and may be important for the survival of bacterial pathogens.// The chaperone function is dominant at low temperatures, whereas the proteolytic activity is turned on at elevated temperatures. [Protein fate, Protein folding and stabilization, Protein fate, Degradation of proteins, peptides, and glycopeptides]

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 694849578   116 RVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHL-EVVKLIKSGAYVALTLL 171
Cdd:TIGR02037  362 KGVVVTKVVSGSPAARAGLQPGDVILSVNQQPVSSVAELrKVLARAKKGGRVALLIL 418

DNA polymerase III subunit gamma/tau;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578 1249 AVGLSSPllPAADDNPTVLLGREQPPALLEEPVSSEVEEGEEELPVAPlPTGAGVEAAATLPAKRPGPPMRLPLPGPVGA 1328
Cdd:PRK07003  361 AVTGGGA--PGGGVPARVAGAVPAPGARAAAAVGASAVPAVTAVTGAA-GAALAPKAAAAAAATRAEAPPAAPAPPATAD 437

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578 1329 EGLAEAAledVENLRLLILRRLLPCRDAEPEDDLTPTPSVIGGAGQAWDS---VLSSQDSASQEVLAEPPSAAEDTKLRS 1405
Cdd:PRK07003  438 RGDDAAD---GDAPVPAKANARASADSRCDERDAQPPADSGSASAPASDAppdAAFEPAPRAAAPSAATPAAVPDARAPA 514

                         170       180       190
                  ....*....|....*....|....*....|...
gi 694849578 1406 GREETDEPGPAAE-EPSGYKGGPRAPKPRRRAT 1437
Cdd:PRK07003  515 AASREDAPAAAAPpAPEARPPTPAAAAPAARAG 547

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 694849578 1035 RLDATSLERTSNPLAAEFKSLDLTSRRMIHEGPLTWRISKDKTVDLHVLLLEDLLVLLQKQDEKLVLKCHSKTALGSSDN 1114
Cdd:cd13391     1 RLDATALERASNPLAAEFKNLDLTTRRMIHEGPLTWRISKDKTLDLHVLLLEDLLVLLQKQDEKLVLKCHSKTAVGSSDS 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 694849578 1115 KQTFSPVLKLNSVLIRSVATDKRALFIICTSELGPQIYELVALTSSEKNTWMELLEEAVQSA 1176
Cdd:cd13391    81 KQTFSPVLKLNSVLIRSVATDKRALFIICTSKLGPQIYELVALTSSEKNTWMELLEEAVRNA 142

Regulator of G protein signaling (RGS) domain found in the Rho guanine nucleotide exchange factor (RhoGEF) protein; The RGS domain found in the Rho guanine nucleotide exchange factor (RhoGEF) protein subfamily of the RGS domain containing protein family, which is a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). RhoGEFs link signals from heterotrimeric G-alpha12/13 protein-coupled receptors to Rho GTPase activation, leading to various cellular responses, such as actin reorganization and gene expression. The RGS domain of the RhoGEFs has very little sequence similarity with the canonical RGS domain of the RGS proteins and therefore is often refered to as the RH (RGS Homology) domain. The RGS-GEFs subfamily includes the leukemia-associated RhoGEF (LARG), p115RhoGEF, and PDZ-RhoGEF. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. RGS proteins regulate many aspects of embryonic development such as glial differentiation, embryonic axis formation, skeletal and muscle development, cell migration during early embryogenesis, as well as apoptosis, cell proliferation, and modulation of cardiac development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  414 KSRPAHLGVFLRYIFSQADPSPLLFYLCTDVCQQTTAKDSRVLGKDIWNIFLDRNAPLRVKVSEQLLVEIETRLRNG--- 490
Cdd:cd08736     1 KSRPAHLAVFLHYVLSQFDPSPLLFYLITDLYKQGNPKDMRKWAYEIYSTFLEKNAPLKVKVPESLAAEIDKRLPNLide 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 694849578  491 DDVRAALFEAQEMVMPEIQEQIQDYRTKRTMGLGSLYGEN 530
Cdd:cd08736    81 EDLRRVFQEAQERAMPEIQEQLEDFRQKRTMGLGSLEGEL 120

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 694849578 1037 DATSLERTSNPLAAEFKSLDLTSRRMIHEGPLTWRISKDKTVDLHVLLLEDLLVLLQKQDEKLVLKCHSKTALGSSDNKQ 1116
Cdd:cd13390     1 DLSSLKQSEYPMIDELRNLDLTKRKMIHEGPLTWKVNRDKTIDLYTLLLEDILVLLQKQDDRLVLRCHSKILASTADSKH 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 694849578 1117 TFSPVLKLNSVLIRSVATDKRALFIICTSELGPQIYELVALTSSEKNTWMELL 1169
Cdd:cd13390    81 TFSPVIKLNTVLVRQVATDNKAFFVISMSENGAQIYELVAQTVSEKTVWQDLI 133

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 694849578   834 VINELFATEGSHLRILRVLDLLFYQRMKKESLLSREELALLFPNLPDLIEIHNSLSesMKKLREEGPIIKEIGDLMLSRF 913
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWISIQRIGDIFLKFA 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578   914 DGLakeeiqQVAADFCSYQSIALELIKTKQRKETRFQIFMQEAESNPQCRRLQLKDLIISEMQRLTKYPLLLENIIKHTE 993
Cdd:pfam00621   79 PGF------KVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTP 152

                          170       180
                   ....*....|....*....|....
gi 694849578   994 AGTSEHDKLCRARDQCRDILKYVN 1017
Cdd:pfam00621  153 PDHPDYEDLKKALEAIKEVAKQIN 176

PDZ domain of ARHGEF11, ARHGEF12, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of ARHGEF11, ARHGEF12, and related domains. This subfamily includes the GEFs (guanine exchange factors) ARHGEF11 (Rho guanine nucleotide exchange factor 11, known as PDZ-RhoGEF) and ARHGEF12 (Rho guanine nucleotide exchange factor 12, also known as leukemia-associated RhoGEF). GEFs activate Rho GTPases by promoting GTP binding. ARHGEF11/12 are regulators of G protein signaling (RGS) domain-containing GEFs; the RGS domain mediates their binding to and activation of Galpha (and Gq also in the case of ARHGEF12), in response to G-protein coupled receptor activation. ARHGEF11 and 12 are involved in serum-signaling, and regulate Yes-Associated Protein (YAP1)-dependent transcription. The ARHGEF12 PDZ domain binds plexin-B1 and the receptor tyrosine kinase insulin-like growth factor receptor (IGF-R1) beta-subunit. ARHGEF12 also interacts with glutamate receptor delta-1(GluD1), a postsynaptic organizer of inhibitory synapses in cortical pyramidal neurons. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This ARHGEF11-12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 694849578   96 QRCVVIQKDQHGFGFTVSGDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIKSGAYVALTLL 171
Cdd:cd23069     1 QRCVVIQRDENGYGLTVSGDNPVFVQSVKEGGAAYRAGVQEGDRIIKVNGTLVTHSNHLEVVKLIKSGSYVALTLL 76

Regulator of G protein signaling (RGS) domain found in the leukemia-associated Rho guanine nucleotide exchange factor (RhoGEF) protein (LARG); The RGS domain is an essential part of the leukemia-associated RhoGEF protein (LARG), a member of the RhoGEF (Rho guanine nucleotide exchange factor) subfamily of the RGS protein family. The RhoGEFs are peripheral membrane proteins that regulate essential cellular processes, including cell shape, cell migration, cell cycle progression of cells, and gene transcription by linking signals from heterotrimeric G-alpha12/13 protein-coupled receptors to Rho GTPase activation, leading to various cellular responses, such as actin reorganization and gene expression. The RhoGEF subfamily includes p115RhoGEF, LARG, PDZ-RhoGEF, and its rat specific splice variant GTRAP48. The RGS domain of RhoGEFs has very little sequence similarity with the canonical RGS domain of the RGS proteins and is often refered to as RH (RGS Homology) domain. In addition to being a G-alpha13 effector, the LARG protein also functions as a GTPase-activating protein (GAP) for G-alpha13. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. RGS proteins regulate many aspects of embryonic development such as glial differentiation, embryonic axis formation, skeletal and muscle development, cell migration during early embryogenesis, as well as apoptosis, cell proliferation, and modulation of cardiac development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  385 IIGPEEDYDPG---YFNNEVMCdslFQDLGKLKSRPAHLGVFLRYIFSQADPSPLLFYLCTDVCQQTTAKDSRVLGKDIW 461
Cdd:cd08754     2 IIGAEDDDFPTeseQINGQCSC---FQNIELLKSRPAHLAVFLHHVVSQFDPAALLCYLYADLYKQTNSKETRRVFLEFN 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  462 NIFLDRNAPLRVKVSEQLLVEIETR---LRNGDDVRAALFEAQEMVMPEIQEQIQDYRTKRTMGLGSLYGENDLLDLDGD 538
Cdd:cd08754    79 QFFLDRAANLKVPVPDEVSLDLEKRrpeLIPEELHRHYIQTMQERVSPEVQRNLEDFRQKRSMGLTLAEGELTKLDAERF 158

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 694849578  539 P-----QKERQVAEKQLAQLGDIL---SKYEEDRSSPMAFALSTYMNHTGIRSREPR 587
Cdd:cd08754   159 RdrntiEKERACAEQIVAKIEEVLmtsQTPEEDKSSTIQYVILTYMKHLGVKVKEPR 215

Regulator of G protein signaling (RGS) domain found in the Rho guanine nucleotide exchange factor (RhoGEF) protein; The RGS domain found in the Rho guanine nucleotide exchange factor (RhoGEF) protein subfamily of the RGS domain containing protein family, which is a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). The RhoGEFs are peripheral membrane proteins that regulate essential cellular processes, including cell shape, cell migration and cell cycle progression as well as gene transcription by linking signals from heterotrimeric G-alpha12/13 protein-coupled receptors to Rho GTPase activation, leading to various cellular responses, such as actin reorganization and gene expression. The RhoGEF subfamily includes the leukemia-associated RhoGEF protein (LARG), p115RhoGEF, PDZ-RhoGEF, and its rat specific splice variant GTRAP48. The RGS domain of RhoGEFs has very little sequence similarity with the canonical RGS domain of the RGS proteins and is often refered to as RH (RGS Homology) domain. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. RGS proteins regulate many aspects of embryonic development such as glial differentiation, embryonic axis formation, skeletal and muscle development, cell migration during early embryogenesis, as well as apoptosis, cell proliferation, and modulation of cardiac development.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578  414 KSRPAHLGVFLRYIFSQADPSPLLFYLCTDVCQQTTAKDSRVLGKDIWNIFLDRNAPL-RVKVSEQLLVEIETRLRNGDD 492
Cdd:cd08756     1 KTHPAHLAVFLNYLLSNSDPSSLFFYLITDLYKSGNIKDMRKWAYEIFSTFLVPNAPLlWPNIDESLIQEIDKILQNEQD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 694849578  493 ----VRAALFEAQEMVMPEIQEQIQDYRTKRTMGLGSLYGEN 530
Cdd:cd08756    81 deeiLRRVFLKAREKARDEINDQLADFRQKRTLGLGSIFGPN 122

PDZ domains of the Na+/H+ exchange regulatory cofactor (NHERF) family (NHERF1-4), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of the Na+/H+ exchange regulatory cofactor (NHERF) family of multi-PDZ-domain-containing scaffolding proteins (NHERF1-4), and related domains. The NHERF family includes NHERF1 (also known as EBP50), NHERF2 (also known as E3KARP; TKA-1; SIP-1), NHERF3 (also known as CAP70; CLAMP; Napi-Cap-1; PDZD1) and NHERF4 (also known as IKEPP; PDZK2; Napi-Cap-2). NHERF1 and NHERF2 have tandem PDZ domains (PDZ1-2); NHERF3 and NHERF4 have four PDZ domains (PDZ1-4). NHERFs are involved in the regulation of multiple receptors or transporters, such as type II sodium-phosphate cotransporter (Npt2a), purinergic P2Y1 receptor P2Y1R, the beta2-adrenergic receptor (beta2-AR), parathyroid hormone receptor type 1 (PTHR), the lysophosphatidic acid receptors (LPARs), sodium-hydrogen exchanger 3 (NHE3), and cystic fibrosis transmembrane conductance regulator (CFTR). NHERF-PDZ1 domain interaction partners include Npt2a, purinergic P2Y1 receptor, beta2-AR, CFTR, PTHR, NH3, G-protein-coupled receptor kinase 6 (GRK6A), platelet-derived growth factor receptor (PDGFR), B1 subunit of the H+ATPase, cholesterol, receptor for activated C-kinase RACK1, aquaporin 9, among others. The NHERF PDZ2 domain interacts with fewer proteins: NHERF1 PDZ2 binds Npt2a, PTHR, beta-catenin, aquaporin 9, and RACK1; NHERF2 PDZ2 binds LPA2, P2Y1R, and NHE3, cGMP-dependent protein kinase type II (cGKII). NHERF4 PDZ1 and PDZ4 bind the epithelial Ca(2+) channels TRPV5 and TRPV6. NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. NHERF4 regulates several transporters mediating influx of xenobiotics and nutrients in the small intestine. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This NHERF-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578   97 RCVVIQKDQHGFGFTVSGDRVV---LVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIK-SGAYVALTLLG 172
Cdd:cd06768     1 RLCHLVKGPEGYGFNLHAEKGRpghFIREVDPGSPAERAGLKDGDRLVEVNGENVEGESHEQVVEKIKaSGNQVTLLVVD 80

PDZ domain of rhophilin-1, rhophilin-2, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of rhophilin-1, rhophilin-2, and related domains. Rhophilin-1 (RHPN1, also known as GTP-Rho-binding protein 1) and rhophilin-2 (RHPN2, also known as GTP-Rho-binding protein 2) are Rho-GTP binding proteins involved in cytoskeletal dynamics. Rhophilin-2 inhibits RhoA's activity to induce F-actin stress fibers. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This rhophilin-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 694849578   97 RCVVIQKDQHGFGFTVSGDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIKS 162
Cdd:cd06712     2 RTVHLTKEEGGFGFTLRGDSPVQVASVDPGSCAAEAGLKEGDYIVSVGGVDCKWSKHSEVVKLLKS 67

PDZ domain 2 of delphilin (L-delphilin isoform), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of delphilin (also known as glutamate receptor, ionotropic, delta 2-interacting protein 1, L-delphilin). Delphilin, a postsynaptic protein which it is selectively expressed at cerebellar Purkinje cells, links the glutamate receptor delta 2 subunit (GluRdelta2) with the actin cytoskeleton and various signaling molecules. Two alternatively spliced isoforms of delphilin have been characterized: L-delphilin has two PDZ domains, PDZ1 and PDZ2, and S-delphilin has a single PDZ domain (PDZ2). These two isoforms are differently palmitoylated and may be involved in controlling GluRdelta2 signaling in Purkinje cells. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This delphilin-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 694849578   99 VVIQKDQHGFGFTVSGDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIK-SGAYVAL 168
Cdd:cd06744     2 VRVYRGNGSFGFTLRGHAPVYIESVDPGSAAERAGLKPGDRILFLNGLDVRNCSHDKVVSLLQgSGSMPTL 72

PDZ domain of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2, SHANK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SHANK1, SHANK2, SHANK3, and related domains. SHANK family proteins, SHANK1 (also known as somatostatin receptor-interacting protein, SSTR-interacting protein, SSTRIP), SHANK2 (also known as cortactin-binding protein 1, proline-rich synapse-associated protein 1), and SHANK3 (proline-rich synapse-associated protein 2) are synaptic scaffolding proteins which are highly enriched in the post-synaptic densities of excitatory synapses. They have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling, and are regulators of Cav1 calcium current and CREB target expression. Many protein ligands have been identified for the Shank PDZ domain, such as GKAP (also known as SAPAP), betaPIX (a guanine nucleotide exchange factor used by Rho GTPase family members Rac1 and Cdc42), alpha-latrotoxin, neuroligin, group I metabotropic glutamate receptors (mGluRs), and L-type calcium channels. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SHANK-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578   97 RCVVIQKDQHGFGFTVSGDRVV----------------LVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLI 160
Cdd:cd06746     7 RTVVLQKGDKGFGFVLRGAKAVgpileftptpafpalqYLESVDPGGVADKAGLKKGDFLLEINGEDVVKASHEQVVNLI 86

                          90
                  ....*....|..
gi 694849578  161 K-SGAYVALTLL 171
Cdd:cd06746    87 RqSGNTLVLKVV 98

PDZ domain; PDZ domains are found in diverse signaling proteins.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578    99 VVIQKD-QHGFGFTVSG-----DRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLIK-SGAYVALTLL 171
Cdd:pfam00595    2 VTLEKDgRGGLGFSLKGgsdqgDPGIFVSEVLPGGAAEAGGLKVGDRILSINGQDVENMTHEEAVLALKgSGGKVTLTIL 81

PDZ domain of regulator of G-protein signaling 12 (RGS12), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RGS12, and related domains. RGS12 downregulates GPCR signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving G-proteins into their inactive GDP-bound form. The RGS12 PDZ domain can bind selectively to C-terminal (A/S)-T-X-(L/V) motifs as found within both the CXCR2 IL-8 receptor, and the alternative 3' exon form of RGS12. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RGS12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 694849578   97 RCVVIQKDQHGFGFTVSGDRVVLVQSVRPGGAAMRAGVQEGDRIVKVNGTMVTNSSHLEVVKLI 160
Cdd:cd06710     1 RTVEIARGRAGYGFTISGQAPCVLSCVVRGSPADVAGLKAGDQILAVNGINVSKASHEDVVKLI 64

Rho guanine nucleotide exchange factor 18 Pleckstrin homology (PH) domain; ARHGEF18, also called p114RhoGEF, is a key regulator of RhoA-Rock2 signaling that is crucial for maintenance of polarity in the vertebrate retinal epithelium, and consequently is essential for cellular differentiation, morphology and eventually organ function. ARHGEF18 contains 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 694849578 1060 RRMIHEGPLTWRISKDKTVDLHVLLLEDLLVLLQKQDEKLVLkchsktalGSSDNKqtfSPVLKLNSVLIRSVATDKRAL 1139
Cdd:cd15794     2 RQLLLEGMLYWKAASGRLKDILALLLTDVLLLLQEKDQKYVF--------ASVDSK---PPVISLQKLIVREVANEEKAM 70

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 694849578 1140 FIICTSELGPQIYELVALTSSEKNTWMELLEEAVQS 1175
Cdd:cd15794    71 FLISASLNGPEMYEIHTNSKEDRNTWMAHIRRAVES 106