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 386768164  934 AENVTFLAIFLNYVISNSDPAPLLFYLITELYKEGTSKDMRKWAYEIHSTFLVPRAPLSWYRQDESLAREVDNVLQLEYD 1013
Cdd:cd08756     1 KTHPAHLAVFLNYLLSNSDPSSLFFYLITDLYKSGNIKDMRKWAYEIFSTFLVPNAPLLWPNIDESLIQEIDKILQNEQD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 386768164 1014 KVEILRTVFLRSRKRAKDLISEQLREFQQKRTAGLGTIYGPT 1055
Cdd:cd08756    81 DEEILRRVFLKAREKARDEINDQLADFRQKRTLGLGSIFGPN 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 386768164 1537 RQEIINEIYQTERNHVRTLKLLDRLFFLPLYESGLLSQDHLLLLFPPALLSLREIHGAFEQSLKQRRIEHNHvvntIGDL 1616
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDK----SGPR 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164 1617 LADMFDGQSGvvLCEFAAQFCARQQIALEALKEKRNKDEMLQKLLKKSESHkaCRRLELKDLLPTVLQRLTKYPLLFENL 1696
Cdd:cd00160    77 IGDVFLKLAP--FFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAESE--CGRLKLESLLLKPVQRLTKYPLLLKEL 152

                         170       180       190
                  ....*....|....*....|....*....|...
gi 386768164 1697 YKVTvrllPENTTEAEAIQRAVESSKRILVEVN 1729
Cdd:cd00160   153 LKHT----PDGHEDREDLKKALEAIKEVASQVN 181

protein kinase C conserved region 1 (C1 domain) found in uncharacterized Rho guanine nucleotide exchange factor (ARHGEF)-like proteins; The family includes a group of uncharacterized proteins that show high sequence similarity to vertebrate Rho guanine nucleotide exchange factors ARHGEF11 and ARHGEF12, which may play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Unlike typical ARHGEF11 and ARHGEF12, members of this family contain a C1 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 386768164 1150 GHPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:cd20832     1 GHQFVLQHYYQVTFCNHCSGLLWGIGYQGYQCSDCEFNIHKQCIEVIEESCPG 53

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 386768164  934 AENVTFLAIFLNYVISNSDPAPLLFYLITELYKEGTSKDMRKWAYEIHSTFLVPRAPLSWYRQDESLAREVDNVLQLEYD 1013
Cdd:cd08756     1 KTHPAHLAVFLNYLLSNSDPSSLFFYLITDLYKSGNIKDMRKWAYEIFSTFLVPNAPLLWPNIDESLIQEIDKILQNEQD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 386768164 1014 KVEILRTVFLRSRKRAKDLISEQLREFQQKRTAGLGTIYGPT 1055
Cdd:cd08756    81 DEEILRRVFLKAREKARDEINDQLADFRQKRTLGLGSIFGPN 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 386768164 1768 LIHDGNLTIKKN--PSVQLHGLLFENMIVLLTKQDDKYYLKNLHTPLSITNKPVSPIMSIDAdTLIRQEAADKNSFFLIK 1845
Cdd:cd13329     1 LIHEGPLTWKVArgKLIEVHVLLLEDLLVLLQKQDDKYLLKLHLTGSFDSKDTKSPVIKLST-LLVREVATDKKAFFLIS 79

                          90       100       110
                  ....*....|....*....|....*....|
gi 386768164 1846 MKTS--QMLELRAPSSSECKTWFKHFSDVA 1873
Cdd:cd13329    80 TSKNgpQMYELVANSSSERKTWIKHISDAV 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 386768164  258 YLTLTVRKDSNGYGMKVSGDNPVFVESVKPGGAAEIAGLVAGDMILRVNGHEVRLEKHPTVVGLIKASTTVELAVK 333
Cdd:cd23069     1 QRCVVIQRDENGYGLTVSGDNPVFVQSVKEGGAAYRAGVQEGDRIIKVNGTLVTHSNHLEVVKLIKSGSYVALTLL 76

protein kinase C conserved region 1 (C1 domain) found in uncharacterized Rho guanine nucleotide exchange factor (ARHGEF)-like proteins; The family includes a group of uncharacterized proteins that show high sequence similarity to vertebrate Rho guanine nucleotide exchange factors ARHGEF11 and ARHGEF12, which may play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Unlike typical ARHGEF11 and ARHGEF12, members of this family contain a C1 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 386768164 1150 GHPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:cd20832     1 GHQFVLQHYYQVTFCNHCSGLLWGIGYQGYQCSDCEFNIHKQCIEVIEESCPG 53

Regulator of G protein signalling-like domain; Members of this family adopt a structure consisting of twelve helices that fold into a compact domain that contains the overall structural scaffold observed in other RGS proteins and three additional helical elements that pack closely to it. Helices 1-9 comprise the RGS (pfam00615) fold, in which helices 4-7 form a classic antiparallel bundle adjacent to the other helices. Like other RGS structures, helices 7 and 8 span the length of the folded domain and form essentially one continuous helix with a kink in the middle. Helices 10-12 form an apparently stable C-terminal extension of the structural domain, and although other RGS proteins lack this structure, these elements are intimately associated with the rest of the structural framework by hydrophobic interactions. Members of the family bind to active G-alpha proteins, promoting GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164   921 ENGPFNNLTRLleAENVTFLAIFLNYVISNSDPAPLLFYLITELYKEGTSKDMRKWAYEIHSTFLVPRAPLSwYRQDESL 1000
Cdd:pfam09128    1 QCSCFQSLEQL--KSRPAHLAVFLHHVVSQFDPSPLLCYLYADLYQQTNSKETRRVFLDIHNFFLEKNAPLR-VPVPESV 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164  1001 AREVDNVlQLEYDKVEILRTVFLRSRKRAKDLISEQLREFQQKRTAGLGTIYGPTD--------DKLAEAKTDKLREQII 1072
Cdd:pfam09128   78 AAELDRR-RPELIPEDLHRRYIQTMQERAVPDIQRQLEDFRQKRSMGLTLAEGELSlldaerdgDRGTLERERRVAEQIL 156

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 386768164  1073 DKylmpnlhalIED--ENGSPPEDVRKVALCSALSTVI 1108
Cdd:pfam09128  157 SK---------IEEilSTSQTFDEERSATIQYVILTYM 185

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 386768164  1151 HPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:pfam00130    1 HHFVHRNFKQPTFCDHCGEFLWGLGKQGLKCSWCKLNVHKRCHEKVPPECGC 52

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 386768164   260 TLTVRKDSNGY-GMKVSG-----DNPVFVESVKPGGAAEIAGLVAGDMILRVNGHEVRLEKHPTVVGLIKASTTV 328
Cdd:pfam00595    1 QVTLEKDGRGGlGFSLKGgsdqgDPGIFVSEVLPGGAAEAGGLKVGDRILSINGQDVENMTHEEAVLALKGSGGK 75

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164  253 PKNFQYLTLTVRKDSNGYGMKVS-GDNPVFVESVKPGGAAEIAGLVAGDMILRVNGHEVRLEKHPTVVGLI--KASTTVE 329
Cdd:COG0793    45 PEEYEDFQESTSGEFGGLGAELGeEDGKVVVVSVIPGSPAEKAGIKPGDIILAIDGKSVAGLTLDDAVKLLrgKAGTKVT 124

                          90
                  ....*....|....*...
gi 386768164  330 LAVKRSQKlTRPSSVSVV 347
Cdd:COG0793   125 LTIKRPGE-GEPITVTLT 141

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 386768164   269 GYGMKVSGDnpVFVESVKPGGAAEIAGLVAGDMILRVNGHEVRLEKH-PTVVGLIKASTTVELAVKR 334
Cdd:TIGR02037  250 SLGLEKQRG--ALVAQVLPGSPAEKAGLKAGDVITSVNGKPISSFADlRRAIGTLKPGKKVTLGILR 314

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 386768164  934 AENVTFLAIFLNYVISNSDPAPLLFYLITELYKEGTSKDMRKWAYEIHSTFLVPRAPLSWYRQDESLAREVDNVLQLEYD 1013
Cdd:cd08756     1 KTHPAHLAVFLNYLLSNSDPSSLFFYLITDLYKSGNIKDMRKWAYEIFSTFLVPNAPLLWPNIDESLIQEIDKILQNEQD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 386768164 1014 KVEILRTVFLRSRKRAKDLISEQLREFQQKRTAGLGTIYGPT 1055
Cdd:cd08756    81 DEEILRRVFLKAREKARDEINDQLADFRQKRTLGLGSIFGPN 122

PH domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164  1754 DKEEFKKLDLTQHHLIHDGNLTIKKNPS--VQLHGLLFENMIVLLTKQDDKYYLKNLHTPLSI-TNKPVSPIMSIDAdTL 1830
Cdd:pfam17838    3 LGEEFKKLDLTTRKLIHEGPLTWRNSKGklVEVHALLLEDILVLLQEKDQKLVLACLSTGSENvDQKTQSPIISLKK-LI 81

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*.
gi 386768164  1831 IRQEAADKNSFFLIKMKTS--QMLELRAPSSSECKTWFKHFSDVAA 1874
Cdd:pfam17838   82 VREVATDKKAFFLISTSPSdpQMYELHASTKSERNTWTKLIQDAIE 127

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 386768164 1537 RQEIINEIYQTERNHVRTLKLLDRLFFLPLYESGLLSQDHLLLLFPPALLSLREIHGAFEQSLKQRRIEHNHvvntIGDL 1616
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDK----SGPR 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164 1617 LADMFDGQSGvvLCEFAAQFCARQQIALEALKEKRNKDEMLQKLLKKSESHkaCRRLELKDLLPTVLQRLTKYPLLFENL 1696
Cdd:cd00160    77 IGDVFLKLAP--FFKIYSEYCSNHPDALELLKKLKKFNKFFQEFLEKAESE--CGRLKLESLLLKPVQRLTKYPLLLKEL 152

                         170       180       190
                  ....*....|....*....|....*....|...
gi 386768164 1697 YKVTvrllPENTTEAEAIQRAVESSKRILVEVN 1729
Cdd:cd00160   153 LKHT----PDGHEDREDLKKALEAIKEVASQVN 181

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 386768164   1540 IINEIYQTERNHVRTLKLLDRLFFLPLYESGLLSQDHLLLLFPPALLSLREIHGAFEQSLKQRRIEHNHvvntIGDLLAD 1619
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDD----SVERIGD 76

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164   1620 MFDGQSGvvLCEFAAQFCARQQIALEALKEKRnKDEMLQKLLKKSESHKACRRLELKDLLPTVLQRLTKYPLLFENLYKV 1699
Cdd:smart00325   77 VFLKLEE--FFKIYSEYCSNHPDALELLKKLK-KNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKH 153

                           170       180       190
                    ....*....|....*....|....*....|.
gi 386768164   1700 TvrllPENTTEAEAIQRAVESSKRILVEVNQ 1730
Cdd:smart00325  154 T----PEDHEDREDLKKALKAIKELANQVNE 180

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 386768164  1540 IINEIYQTERNHVRTLKLLDRLFFLPLYESgllsqdhllllfppALLSLREIHGAF----------EQSLKQRRIEHNHV 1609
Cdd:pfam00621    1 VIKELLQTERSYVRDLEILVEVFLPPNSKP--------------LSESEEEIKTIFsnieeiyelhRQLLLEELLKEWIS 66

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164  1610 VNTIGDLLADMFDGQsgvvlcEFAAQFCARQQIALEALKEKRNKDEMLQKLLKKSESHKACRRLELKDLLPTVLQRLTKY 1689
Cdd:pfam00621   67 IQRIGDIFLKFAPGF------KVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRY 140

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|
gi 386768164  1690 PLLFENLYKVTvrllPENTTEAEAIQRAVESSKRILVEVN 1729
Cdd:pfam00621  141 PLLLKELLKHT----PPDHPDYEDLKKALEAIKEVAKQIN 176

Regulator of G protein signaling (RGS) domain found in the PDZ-Rho guanine nucleotide exchange factor (RhoGEF) protein; The RGS domain is an essential part of the PDZ-RhoGEF (PDZ:Postsynaptic density 95, Disk large, Zona occludens-1; RhoGEF: Rho guanine nucleotide exchange factor; alias PRG) protein, a member of RhoGEFs subfamily of the RGS protein family. 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. RhoGEFs subfamily includes 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. In contrast to p115RhoGEF and LARG, PDZ-RhoGEF cannot serve as a GTPase-activating protein (GAP), due to the mutation of sites in the RGS domain region that are crucial for GAP activity. 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 386768164  904 IISMEdENSDLDEPFIDENGPFNNLTRLleAENVTFLAIFLNYVISNSDPAPLLFYLITELYKEGTSKDMRKWAYEIHST 983
Cdd:cd08753     2 IIGPE-EDYDPGYFNNESDIIFQDLEKL--KSRPAHLVVFLRYIFSQADPGPLLFYLCSEVYQQTSPKDSRSLGKDIWNI 78

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164  984 FLVPRAPLSwYRQDESLAREVDNVLQLEYDkveiLRTVFLRSRKRAKDLISEQLREFQQKRTAGLGTIYG 1053
Cdd:cd08753    79 FLEKNAPLR-VKIPEMLQAEIDLRLRNNED----PRGVLCEAQEAVMPEIQEQIQDYRSKRTLGLGSLYG 143

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 386768164 1756 EEFKKLDLTQHHLIHDGNLTIK--KNPSVQLHGLLFENMIVLLTKQDDKYYLKNLHTPLSITNKP---VSPIMSIDAdTL 1830
Cdd:cd13390    14 DELRNLDLTKRKMIHEGPLTWKvnRDKTIDLYTLLLEDILVLLQKQDDRLVLRCHSKILASTADSkhtFSPVIKLNT-VL 92

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 386768164 1831 IRQEAADKNSFFLIKMKT--SQMLELRAPSSSECKTW 1865
Cdd:cd13390    93 VRQVATDNKAFFVISMSEngAQIYELVAQTVSEKTVW 129

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 386768164  260 TLTVRKDSNGYGMKVSGDNPVFVESVKPGGAAEIAGLVAGDMILRVNGHEVRLEKHPTVVGLIKAS 325
Cdd:cd06744     1 TVRVYRGNGSFGFTLRGHAPVYIESVDPGSAAERAGLKPGDRILFLNGLDVRNCSHDKVVSLLQGS 66

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 386768164  1151 HPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:pfam00130    1 HHFVHRNFKQPTFCDHCGEFLWGLGKQGLKCSWCKLNVHKRCHEKVPPECGC 52

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 386768164 1151 HPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESC 1200
Cdd:cd00029     1 HRFVPTTFSSPTFCDVCGKLIWGLFKQGLKCSDCGLVCHKKCLDKAPSPC 50

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 386768164 1150 GHPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:cd20792     1 GHKFVATFFKQPTFCSHCKDFIWGLGKQGYQCQVCRFVVHKRCHEYVVFKCPG 53

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 386768164  260 TLTVRKDSN-GYGMKVSG----DNPVFVESVKPGGAAEIAG-LVAGDMILRVNGHEVRLEKHPTVVGLIK-ASTTVELAV 332
Cdd:cd00136     1 TVTLEKDPGgGLGFSIRGgkdgGGGIFVSRVEPGGPAARDGrLRVGDRILEVNGVSLEGLTHEEAVELLKsAGGEVTLTV 80

                  .
gi 386768164  333 K 333
Cdd:cd00136    81 R 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 386768164  260 TLTVRKDSNGYGMKVSGDNPVFVESVKPGGAAEIAGLVAGDMILRVNGHEVRLEKHPTVVGLIKASTTV 328
Cdd:cd06710     2 TVEIARGRAGYGFTISGQAPCVLSCVVRGSPADVAGLKAGDQILAVNGINVSKASHEDVVKLIGKCTGV 70

second protein kinase C conserved region 1 (C1 domain) found in the family of protein kinase D (PKD); PKDs are important regulators of many intracellular signaling pathways such as ERK and JNK, and cellular processes including the organization of the trans-Golgi network, membrane trafficking, cell proliferation, migration, and apoptosis. They are activated in a PKC-dependent manner by many agents including diacylglycerol (DAG), PDGF, neuropeptides, oxidative stress, and tumor-promoting phorbol esters, among others. Mammals harbor three types of PKDs: PKD1 (or PKCmu), PKD2, and PKD3 (or PKCnu). PKDs contain N-terminal tandem cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. This model corresponds to the second 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 386768164 1151 HPLVLRQYYEVTHCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:cd20796     2 HTFVVHTYTKPTVCQHCKKLLKGLFRQGLQCKDCKFNCHKKCAEKVPKDCTG 53

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 386768164  903 EIISMEDENSDLDEPFIdeNGP---FNNLtRLLEAENvTFLAIFLNYVISNSDPAPLLFYLITELYKEGTSKDMRKWAYE 979
Cdd:cd08754     1 GIIGAEDDDFPTESEQI--NGQcscFQNI-ELLKSRP-AHLAVFLHHVVSQFDPAALLCYLYADLYKQTNSKETRRVFLE 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386768164  980 IHSTFLVPRAPLSWYRQDESlarevdnVLQLEYDKVEIL-----RTVFLRSRKRAKDLISEQLREFQQKRTAGLGTIYGP 1054
Cdd:cd08754    77 FNQFFLDRAANLKVPVPDEV-------SLDLEKRRPELIpeelhRHYIQTMQERVSPEVQRNLEDFRQKRSMGLTLAEGE 149

                         170       180
                  ....*....|....*....|....*...
gi 386768164 1055 TD--------DKLAEAKTDKLREQIIDK 1074
Cdd:cd08754   150 LTkldaerfrDRNTIEKERACAEQIVAK 177

protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins; RASGRP4 functions as a cation- and diacylglycerol (DAG)-regulated nucleotide exchange factor activating Ras through the exchange of bound GDP for GTP. It may function in mast cell differentiation. 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
                  ....*....|....*....|....*....|....*....
gi 386768164 1162 THCNHCQTIIWGVSPQGYHCTDCKLNIHRQCSKVVDESC 1200
Cdd:cd20863    15 TFCDSCSGFLWGVTKQGYRCQDCGINCHKHCKDQVDVEC 53

first protein kinase C conserved region 1 (C1 domain) found in novel protein kinase C (nPKC) epsilon, eta, 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. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-epsilon has been shown to behave as an oncoprotein. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumor invasion and metastasis. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility. PKC-eta is predominantly expressed in squamous epithelia, where it plays a crucial role in the signaling of cell-type specific differentiation. It is also expressed in pro-B cells and early-stage thymocytes, and acts as a key regulator in early B-cell development. PKC-eta increases glioblastoma multiforme (GBM) proliferation and resistance to radiation, and is being developed as a therapeutic target for the management of GBM. 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 386768164 1148 VRGHPLV---LRQYyevTHCNHCQTIIWGV-SPQGYHCTDCKLNIHRQCSKVVDESCPG 1202
Cdd:cd20835     7 VNGHKFMatyLRQP---TYCSHCKDFIWGViGKQGYQCQVCTCVVHKRCHQLVVTKCPG 62