Rho guanine nucleotide exchange factor Pleckstrin homology domain; 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 1832392673  985 LVHDGPLTCRFNRGKMVELHVVLLENMLVLLTKHSDGNKL-QLKTLEPSKETKWSPILPLAPLIAKEKANDKRAFFLVFN 1063
Cdd:cd13329      1 LIHEGPLTWKVARGKLIEVHVLLLEDLLVLLQKQDDKYLLkLHLTGSFDSKDTKSPVIKLSTLLVREVATDKKAFFLIST 80

                           90       100
                   ....*....|....*....|....*....
gi 1832392673 1064 SQYGAQIYELVAGTATERKTWFKLMSDQI 1092
Cdd:cd13329     81 SKNGPQMYELVANSSSERKTWIKHISDAV 109

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 1832392673   51 ERCVVVQRQAEGFGLTVTGDYPVYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRMISGGQNVALTLL 126
Cdd:cd23069      1 QRCVVIQRDENGYGLTVSGDNPVFVQSVKEGGAAYRAGVQEGDRIIKVNGTLVTHSNHLEVVKLIKSGSYVALTLL 76

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  257 KTHPAHLAVFINYLLTNANPSSLFFYLITDAYQSayGTAKEFRRWAFEIFSTFIIPNSPMCIPNSDQSIIQPIDKIMCMt 336
Cdd:cd08756      1 KTHPAHLAVFLNYLLSNSDPSSLFFYLITDLYKS--GNIKDMRKWAYEIFSTFLVPNAPLLWPNIDESLIQEIDKILQN- 77

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 1832392673  337 aehiGDSDADTLKRVFVPGRQRAVTDINVHLNEFRQKKQLGGQVSESSN 385
Cdd:cd08756     78 ----EQDDEEILRRVFLKAREKARDEINDQLADFRQKRTLGLGSIFGPN 122

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 1832392673  745 RQEVINELFHTERTHVRNLKILYHLFYKPIVQ-NKVVSSDVAKLLFANLEDLLALHQKMSDAMRAAVEKWkiepphingg 823
Cdd:cd00160      1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKeLLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEW---------- 70

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  824 iyGDIGELMESLFEGEAGekLMLVTATFCQHQQHALEFLRSrcKREKDDALVRFLSEAESNpvCRKLQLKDMIPVEMQRL 903
Cdd:cd00160     71 --DKSGPRIGDVFLKLAP--FFKIYSEYCSNHPDALELLKK--LKKFNKFFQEFLEKAESE--CGRLKLESLLLKPVQRL 142

                          170       180       190
                   ....*....|....*....|....*....|....*....
gi 1832392673  904 VKYPLLLETIAKYTAEPSEEQDRLLRTVVSAKRILSAVN 942
Cdd:cd00160    143 TKYPLLLKELLKHTPDGHEDREDLKKALEAIKEVASQVN 181

PH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  970 FSGHDYASLNLTKYRLVHDGPLTCRFNRGKMVELHVVLLENMLVLLTKHsdGNKLQLKTLEP----SKETKWSPILPLAP 1045
Cdd:pfam17838    2 PLGEEFKKLDLTTRKLIHEGPLTWRNSKGKLVEVHALLLEDILVLLQEK--DQKLVLACLSTgsenVDQKTQSPIISLKK 79

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1832392673 1046 LIAKEKANDKRAFFLVFNSQYGAQIYELVAGTATERKTWFKLMSDQIE 1093
Cdd:pfam17838   80 LIVREVATDKKAFFLISTSPSDPQMYELHASTKSERNTWTKLIQDAIE 127

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 1832392673   748 VINELFHTERTHVRNLKILYHLFYKPIVQ-NKVVSSDVAKLLFANLEDLLALHQKMSDAMRAAVEKWkiepphinggiyG 826
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKeLKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEW------------D 68

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673   827 DIGELMESLFEGEAGEKLMLvtATFCQHQQHALEFLrsrCKREKDDALVRFLSEAESNPVCRKLQLKDMIPVEMQRLVKY 906
Cdd:smart00325   69 DSVERIGDVFLKLEEFFKIY--SEYCSNHPDALELL---KKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKY 143

                           170       180       190
                    ....*....|....*....|....*....|....*.
gi 1832392673   907 PLLLETIAKYTAEPSEEQDRLLRTVVSAKRILSAVN 942
Cdd:smart00325  144 PLLLKELLKHTPEDHEDREDLKKALKAIKELANQVN 179

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  706 QFSS--FMDGDSDFELETEATPLEqlvgwdVIRHLKPKEKKRQEVINELFHTERTHVRNLKILYHLFYKPIVQNKVVSSD 783
Cdd:COG5422    450 RNSSlaLDKFDEEKNLWTLSVPKE------VWESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPEN 523

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  784 V----AKLLFANLEDLLALHQKMSDAMRaaveKWKIEPPHINGgiYGDIGELMESLFEgeagEKLMLVTatfcqhQQHAL 859
Cdd:COG5422    524 ArrnfIKHVFANINEIYAVNSKLLKALT----NRQCLSPIVNG--IADIFLDYVPKFE----PFIKYGA------SQPYA 587

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  860 EFLRSRcKREKDDALVRFLSEAESNPVCRKLQLKDMIPVEMQRLVKYPLLLETIAKYTAEPSEEQDRLLRTVVSAKRILS 939
Cdd:COG5422    588 KYEFER-EKSVNPNFARFDHEVERLDESRKLELDGYLTKPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLS 666

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  940 AVNTAKRNAENLRRLEELQKRIDTTPfdkefsghDYASLNL--TKYRLVHDGPLTCR---FNRGKMV-ELHVVLLENMLV 1013
Cdd:COG5422    667 RLNFESGKAENRGDLFHLNQQLLFKP--------EYVNLGLndEYRKIIFKGVLKRKaksKTDGSLRgDIQFFLLDNMLL 738

                   ..
gi 1832392673 1014 LL 1015
Cdd:COG5422    739 FC 740

protein kinase C conserved region 1 (C1 domain) superfamily; 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 the motif HX12CX2CXnCX2CX4HX2CX7C, where C and H are cysteine and histidine, respectively; X represents other residues; and n is either 13 or 14. C1 has a globular fold with two separate Zn(2+)-binding sites. It was originally discovered as lipid-binding modules in protein kinase C (PKC) isoforms. C1 domains that bind and respond to phorbol esters (PE) and diacylglycerol (DAG) are referred to as typical, and those that do not respond to PE and DAG are deemed atypical. A C1 domain may also be referred to as PKC or non-PKC C1, based on the parent protein's activity. Most C1 domain-containing non-PKC proteins act as lipid kinases and scaffolds, except PKD which acts as a protein kinase. PKC C1 domains play roles in membrane translocation and activation of the enzyme.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1832392673  485 HSFTISSVNTVHYCYQCRDAIWGMQPWIYFCSNCDVKVHPQCTSSLTDAC 534
Cdd:cd00029      1 HRFVPTTFSSPTFCDVCGKLIWGLFKQGLKCSDCGLVCHKKCLDKAPSPC 50

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1832392673   57 QRQAEGFGLTVT--GDYpVYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRMISG--GQNVALTLL 126
Cdd:COG0793     56 SGEFGGLGAELGeeDGK-VVVVSVIPGSPAEKAGIKPGDIILAIDGKSVAGLTLDDAVKLLRGkaGTKVTLTIK 128

Phorbol esters/diacylglycerol binding domain (C1 domain); This domain is also known as the Protein kinase C conserved region 1 (C1) domain.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1832392673  485 HSFTISSVNTVHYCYQCRDAIWG--MQpwIYFCSNCDVKVHPQCTSSLTDAC 534
Cdd:pfam00130    1 HHFVHRNFKQPTFCDHCGEFLWGlgKQ--GLKCSWCKLNVHKRCHEKVPPEC 50

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  257 KTHPAHLAVFINYLLTNANPSSLFFYLITDAYQSayGTAKEFRRWAFEIFSTFIIPNSPMCIPNSDQSIIQPIDKIMCMt 336
Cdd:cd08756      1 KTHPAHLAVFLNYLLSNSDPSSLFFYLITDLYKS--GNIKDMRKWAYEIFSTFLVPNAPLLWPNIDESLIQEIDKILQN- 77

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 1832392673  337 aehiGDSDADTLKRVFVPGRQRAVTDINVHLNEFRQKKQLGGQVSESSN 385
Cdd:cd08756     78 ----EQDDEEILRRVFLKAREKARDEINDQLADFRQKRTLGLGSIFGPN 122

Rho guanine nucleotide exchange factor Pleckstrin homology domain; 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 1832392673  985 LVHDGPLTCRFNRGKMVELHVVLLENMLVLLTKHSDGNKL-QLKTLEPSKETKWSPILPLAPLIAKEKANDKRAFFLVFN 1063
Cdd:cd13329      1 LIHEGPLTWKVARGKLIEVHVLLLEDLLVLLQKQDDKYLLkLHLTGSFDSKDTKSPVIKLSTLLVREVATDKKAFFLIST 80

                           90       100
                   ....*....|....*....|....*....
gi 1832392673 1064 SQYGAQIYELVAGTATERKTWFKLMSDQI 1092
Cdd:cd13329     81 SKNGPQMYELVANSSSERKTWIKHISDAV 109

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 1832392673   51 ERCVVVQRQAEGFGLTVTGDYPVYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRMISGGQNVALTLL 126
Cdd:cd23069      1 QRCVVIQRDENGYGLTVSGDNPVFVQSVKEGGAAYRAGVQEGDRIIKVNGTLVTHSNHLEVVKLIKSGSYVALTLL 76

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 1832392673  748 VINELFHTERTHVRNLKILYHLFYKPIVQNKVVSSDVAKLLFANLEDLLALHQKMSdamraavekwkIEPPHINGGIYGD 827
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL-----------LEELLKEWISIQR 69

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673  828 IGELMESLFEGeageklMLVTATFCQHQQHALEFLRSrcKREKDDALVRFLSEAESNPVCRKLQLKDMIPVEMQRLVKYP 907
Cdd:pfam00621   70 IGDIFLKFAPG------FKVYSTYCSNYPKALKLLKK--LLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYP 141

                          170       180       190
                   ....*....|....*....|....*....|....*
gi 1832392673  908 LLLETIAKYTAEPSEEQDRLLRTVVSAKRILSAVN 942
Cdd:pfam00621  142 LLLKELLKHTPPDHPDYEDLKKALEAIKEVAKQIN 176

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 1832392673  960 RIDTTPFDKEFS--GHDYASLNLTKYRLVHDGPLTCRFNRGKMVELHVVLLENMLVLLTKHSDgnKLQLK----TLEPSK 1033
Cdd:cd13391      1 RLDATALERASNplAAEFKNLDLTTRRMIHEGPLTWRISKDKTLDLHVLLLEDLLVLLQKQDE--KLVLKchskTAVGSS 78

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1832392673 1034 ETK--WSPILPLAPLIAKEKANDKRAFFLVFNSQYGAQIYELVAGTATERKTWFKLMSDQI 1092
Cdd:cd13391     79 DSKqtFSPVLKLNSVLIRSVATDKRALFIICTSKLGPQIYELVALTSSEKNTWMELLEEAV 139

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 1832392673  977 SLNLTKYRLVHDGPLTCRFNRGKMVELHVVLLENMLVLLTKHSDgnKLQL----KTLEPSKETK--WSPILPLAPLIAKE 1050
Cdd:cd13390     18 NLDLTKRKMIHEGPLTWKVNRDKTIDLYTLLLEDILVLLQKQDD--RLVLrchsKILASTADSKhtFSPVIKLNTVLVRQ 95

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1832392673 1051 KANDKRAFFLVFNSQYGAQIYELVAGTATERKTWFKLMS 1089
Cdd:cd13390     96 VATDNKAFFVISMSENGAQIYELVAQTVSEKTVWQDLIT 134

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1832392673   54 VVVQRQAEGFGLTVTGDYPVYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRMISG 117
Cdd:cd06744      2 VRVYRGNGSFGFTLRGHAPVYIESVDPGSAAERAGLKPGDRILFLNGLDVRNCSHDKVVSLLQG 65

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains 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        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673   54 VVVQRQA-EGFGLTVTG----DYPVYVHTVKPDGAAYCAG-VRQGDRIVKVNGMPVTNGNHHEVVRMI-SGGQNVALTLL 126
Cdd:cd00136      2 VTLEKDPgGGLGFSIRGgkdgGGGIFVSRVEPGGPAARDGrLRVGDRILEVNGVSLEGLTHEEAVELLkSAGGEVTLTVR 81

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 1832392673   485 HSFTISSVNTVHYCYQCRDAIWGMQPWIYFCSNCDVKVHPQCTSSLTDAC 534
Cdd:smart00109    1 HKHVFRTFTKPTFCCVCRKSIWGSFKQGLRCSECKVKCHKKCADKVPKAC 50

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673   51 ERCVVVQRQAEGFGLTVTG--------------DYPV--YVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRM 114
Cdd:cd06746      6 PRTVVLQKGDKGFGFVLRGakavgpileftptpAFPAlqYLESVDPGGVADKAGLKKGDFLLEINGEDVVKASHEQVVNL 85

                           90
                   ....*....|...
gi 1832392673  115 I-SGGQNVALTLL 126
Cdd:cd06746     86 IrQSGNTLVLKVV 98

protein kinase C conserved region 1 (C1 domain) superfamily; 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 the motif HX12CX2CXnCX2CX4HX2CX7C, where C and H are cysteine and histidine, respectively; X represents other residues; and n is either 13 or 14. C1 has a globular fold with two separate Zn(2+)-binding sites. It was originally discovered as lipid-binding modules in protein kinase C (PKC) isoforms. C1 domains that bind and respond to phorbol esters (PE) and diacylglycerol (DAG) are referred to as typical, and those that do not respond to PE and DAG are deemed atypical. A C1 domain may also be referred to as PKC or non-PKC C1, based on the parent protein's activity. Most C1 domain-containing non-PKC proteins act as lipid kinases and scaffolds, except PKD which acts as a protein kinase. PKC C1 domains play roles in membrane translocation and activation of the enzyme.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1832392673  485 HSFTISSVNTVHYCYQCRDAIWGMQPWIYFCSNCDVKVHPQCTSSLTDAC 534
Cdd:cd00029      1 HRFVPTTFSSPTFCDVCGKLIWGLFKQGLKCSDCGLVCHKKCLDKAPSPC 50

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 1832392673   52 RCVVVQRQAEGFGLTVTGDYPVYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRMI 115
Cdd:cd06710      1 RTVEIARGRAGYGFTISGQAPCVLSCVVRGSPADVAGLKAGDQILAVNGINVSKASHEDVVKLI 64

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. 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 SNX27-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        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1832392673   52 RCVVVQRQAEGFGLTVTGD--------------YP--VYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVVRMI 115
Cdd:cd23070      1 RVVTIVKSETGFGFNVRGQvseggqlrsingelYAplQHVSAVLEGGAADKAGVRKGDRILEVNGVNVEGATHKQVVDLI 80

                           90
                   ....*....|..
gi 1832392673  116 -SGGQNVALTLL 126
Cdd:cd23070     81 kSGGDELTLTVI 92

PDZ domain 1 of Drosophila Scribble, human Scribble homolog, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of Drosophila Scribble (also known as LAP4), human Scribble homolog (also known as hScrib, LAP4, CriB1, ScrB1 and Vartul), and related domains. They belong to the LAP family, which describes proteins that contain either one or four PDZ domains and 16 LRRs (leucine-rich repeats) and function in controlling cell shape, size and subcellular protein localization. In Drosophila, the Scribble complex, comprising Scribble, discs large, and lethal giant larvae, plays a role in apico-basal cell polarity, in other forms of polarity, including regulation of the actin cytoskeleton, cell signaling and vesicular trafficking, and in tumor development. Mammalian Scribble is important in many aspects of cancer development. Scribble and its homologs can be downregulated or overexpressed in cancer; they have a role in cancer beyond their function in loss of cell polarity. 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 Scribble-like family PDZ1 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 1832392673   54 VVVQRQAEGFGLTVTG----------DYPVYVHTVKPDGAAYCAGVRQGDRIVKVNGMPVTNGNHHEVV 112
Cdd:cd06704      3 ITIERQTGGLGISIAGgkgstpykgdDEGIFISRVTEGGPAAKAGVRVGDKLLEVNGVDLVDADHHEAV 71

PDZ domain 2 of partitioning defective 3 (Par3), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of Par3 (or PAR3 or Par-3, also known as Atypical PKC isotype-specific-interacting protein, ASIP, Drosophila Bazooka) and related domains. Par3 is a scaffold protein involved in organizing cell polarity across animals. Par3 binds numerous molecules both for its recruitment to one pole of the cell and for downstream contributions to polarized cell function. It regulates cell polarity by targeting the Par complex proteins Par6 and atypical protein kinase C (aPKC) to specific cortical sites. Physical interactions between Par3 and the Par complex include Par3 PDZ domain 1 binding to the Par6 PDZ domain, Par3 PDZ domain 1 and PDZ domain 3 binding the Par6's PDZ-binding motif, and an interaction with an undefined region of aPKC that requires both Par3 PDZ2 and PDZ3. The PDZ domains of Par3 have also been implicated as potential phosphoinositide signaling integrators, since its second PDZ domain binds to phosphoinositides, and the third PDZ interacts with phosphoinositide phosphatase PTEN. 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 Par3 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 1832392673   60 AEGFGLTVT-------GDYPVYVHTVKPDGAAYCAG-VRQGDRIVKVNGMPVTNGNHHEVVRMISG---GQNVAL 123
Cdd:cd23058     14 PEGLGFSITsrdnptgGSGPIYIKNILPKGAAIQDGrLKAGDRLLEVNGVDVTGKTQEEVVSLLRStklGGTVSL 88