Regulator of G protein signaling (RGS) domain superfamily; The RGS domain is an essential part of the Regulator of G-protein Signaling (RGS) protein family, a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). RGS proteins play critical regulatory roles as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. While inactive, G-alpha-subunits bind GDP, which is released and replaced by GTP upon agonist activation. GTP binding leads to dissociation of the alpha-subunit and the beta-gamma-dimer, allowing them to interact with effectors molecules and propagate signaling cascades associated with cellular growth, survival, migration, and invasion. Deactivation of the G-protein signaling controlled by the RGS domain accelerates GTPase activity of the alpha subunit by hydrolysis of GTP to GDP, which results in the reassociation of the alpha-subunit with the beta-gamma-dimer and thereby inhibition of downstream activity. As a major G-protein regulator, RGS domain containing proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis. RGS proteins are also involved in apoptosis and cell proliferation, as well as modulation of cardiac development. Several RGS proteins can fine-tune immune responses, while others play important roles in neuronal signals modulation. Some RGS proteins are principal elements needed for proper vision.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767929111  52 DYSSLCDKQPIGRRLFRQFCDTKPTLKRHIEFLDAVAEYEVADDEDRSDCGLSILDRFFNDKLAAPLPEIPPDVVTECRL 131
Cdd:cd08750    1 DYSSLCDKQPIGRLLFRQFCDTRPTLKRCIEFLDAVAEYEVAPDEKRSDCGLSILDTYFNNGSAAHLPEIPQDVVTECRL 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 767929111 132 GLkEENPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQFLQWKWLERQPVTK 184
Cdd:cd08750   81 KL-EENPSKELFEECTRVVHEYLSGEPFEAYQESMYFSRFLQWKWLERQPVTK 132

Regulator of G protein signaling domain (RGS) found in G protein-coupled receptor kinase 4 (GRK4); The RGS domain is an essential part of the GRK4 (G protein-coupled receptor kinase4) proteins, which are membrane-associated serine/threonine protein kinases that phosphorylate G protein-coupled receptors (GPCRs) upon agonist stimulation. This phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events. GRK4 is a member of the GRK kinase family which includes three major subfamilies: the GRK4 subfamily (GRK4, GRK5 and GRK6), the rhodopsin kinase or visual GRK subfamily (GRK1 and GRK7), and the beta-adrenergic receptor kinases subfamily (GRK2/GRK3). The RGS domain of the GRKs 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. GRK4 plays a key role in regulating dopaminergic-mediated natriuresis and is associated with essential hypertension and/or salt-sensitive hypertension. GRK4 exists in four splice variants involved in hyperphosphorylation, desensitization, and internalization of two dopamine receptors (D1R and D3R). GRK4 also increases the expression of a key receptor of the renin-angiotensin system, the AT1R (angiotensin type 1 receptor). 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 767929111  52 DYSSLCDKQPIGRRLFRQFCDTKPTLKRHIEFLDAVAEYEVADDEDRSDCGLSILDRFFNDKLAAPLPEIPPDVVTECRL 131
Cdd:cd08750    1 DYSSLCDKQPIGRLLFRQFCDTRPTLKRCIEFLDAVAEYEVAPDEKRSDCGLSILDTYFNNGSAAHLPEIPQDVVTECRL 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 767929111 132 GLkEENPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQFLQWKWLERQPVTK 184
Cdd:cd08750   81 KL-EENPSKELFEECTRVVHEYLSGEPFEAYQESMYFSRFLQWKWLERQPVTK 132

Regulator of G protein signaling domain; RGS family members are GTPase-activating proteins for heterotrimeric G-protein alpha-subunits.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767929111   52 DYSSLCDKQPiGRRLFRQFCDTKpTLKRHIEFLDAVAEYEVAD-DEDRSDCGLSILDRFFNDKLAAPLpEIPPDVVTECR 130
Cdd:pfam00615   1 SFDSLLEDQP-GRRLFRQFLESE-FSEENLEFWLACEEFKKADpDEERLKKAKEIYNEFLAPGSPKEI-NLDSDLREEIR 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 767929111  131 LGLKEEnPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQF 171
Cdd:pfam00615  78 ENLEKE-PTRDLFDEAQAEVYELMEKDSYPRFLKSPLYLRL 117

Regulator of G protein signaling domain (RGS) found in G protein-coupled receptor kinase 4 (GRK4); The RGS domain is an essential part of the GRK4 (G protein-coupled receptor kinase4) proteins, which are membrane-associated serine/threonine protein kinases that phosphorylate G protein-coupled receptors (GPCRs) upon agonist stimulation. This phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events. GRK4 is a member of the GRK kinase family which includes three major subfamilies: the GRK4 subfamily (GRK4, GRK5 and GRK6), the rhodopsin kinase or visual GRK subfamily (GRK1 and GRK7), and the beta-adrenergic receptor kinases subfamily (GRK2/GRK3). The RGS domain of the GRKs 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. GRK4 plays a key role in regulating dopaminergic-mediated natriuresis and is associated with essential hypertension and/or salt-sensitive hypertension. GRK4 exists in four splice variants involved in hyperphosphorylation, desensitization, and internalization of two dopamine receptors (D1R and D3R). GRK4 also increases the expression of a key receptor of the renin-angiotensin system, the AT1R (angiotensin type 1 receptor). 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 767929111  52 DYSSLCDKQPIGRRLFRQFCDTKPTLKRHIEFLDAVAEYEVADDEDRSDCGLSILDRFFNDKLAAPLPEIPPDVVTECRL 131
Cdd:cd08750    1 DYSSLCDKQPIGRLLFRQFCDTRPTLKRCIEFLDAVAEYEVAPDEKRSDCGLSILDTYFNNGSAAHLPEIPQDVVTECRL 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 767929111 132 GLkEENPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQFLQWKWLERQPVTK 184
Cdd:cd08750   81 KL-EENPSKELFEECTRVVHEYLSGEPFEAYQESMYFSRFLQWKWLERQPVTK 132

Regulator of G protein signaling domain (RGS) found in G protein-coupled receptor kinase (GRK); The RGS domain is found in G protein-coupled receptor kinases (GRKs). These proteins play a key role in phosphorylation-dependent desensitization/resensitization of GPCRs (G protein-coupled receptors), intracellular trafficking, endocytosis, as well as in the modulation of important intracellular signaling cascades by GPCR. GRKs also modulate cellular response in phosphorylation-independent manner using their ability to interact with multiple signaling proteins involved in many essential cellular pathways. The RGS domain of the GRKs 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. Based on sequence homology the GRK family consists of three major subfamilies: the GRK4 subfamily (GRK4, GRK5 and GRK6), the rhodopsin kinase or visual GRK subfamily (GRK1 and GRK7), and the beta-adrenergic receptor kinases subfamily (GRK2/GRK3). 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 767929111  56 LCDKQPIGRRLFRQFCDTKPTLKRHIEFLDAVAEYEVADDEDRSDCGLSILDRFFNDKLAAPLPEIPPDVVTECRLGLkE 135
Cdd:cd08724    1 ICEQQPIGRLLFRQFCETRPELVPQIEFLDEIKEYEVAEDEERAKKAREIYDKYIMKESLAHSHEFSKDAVEHVQENL-E 79

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 767929111 136 ENPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQ 170
Cdd:cd08724   80 KEVPKDLFQPYIEEIHDYLRGAPFQKFLESDYFTR 114

Regulator of G protein signaling domain (RGS) found in G protein-coupled receptor kinase 7 (GRK7); The RGS domain is an essential part of the GRK7 (G protein-coupled receptor kinases 7) proteins which together with GRK1 (Rhodopsin kinase) have been implicated in the shutoff of the photoresponse and adaptation to changing light conditions via rod and cone opsin phosphorylation. GRK7 is a member of the GRK kinase family which includes three major subfamilies: the GRK4 subfamily (GRK4, GRK5 and GRK6), the rhodopsin kinase or visual GRK subfamily (GRK1 and GRK7), and the beta-adrenergic receptor kinases subfamily (GRK2/GRK3). The RGS domain of the GRKs 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. GRK7 is expressed in all vertebrate cones except that of mice and rats, which do not have the gene for GRK7. Lack of either GRK7 or both GRK1 and GRK7 in human leads to a vision defect called Enhanced S Cone syndrome. 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 767929111  37 PPVSQCSELRHSIEKDYSSLCDKQPIGRRLFRQFCDTKPTLKRHIEFLDAVAEYEVADDEDRSDCGLSILDRFFNDKLAA 116
Cdd:cd08749    1 PKPEQCAELRQSLSKDFESLCEQQPIGKRLFRDFLATVPEYTVAADFLDDVQNWELAEEAAKDKARQNIIANFCKAGSKN 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 767929111 117 PLPEIPPDVVTECRLGLKEEnpSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQFLQWK 175
Cdd:cd08749   81 PLSFLSGDVATKCKAATEKD--FEEVVGQAKDETKEFLQGKPFTDFQTSPFYDKFLQWK 137

Regulator of G protein signaling domain; RGS family members are GTPase-activating proteins for heterotrimeric G-protein alpha-subunits.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767929111   52 DYSSLCDKQPiGRRLFRQFCDTKpTLKRHIEFLDAVAEYEVAD-DEDRSDCGLSILDRFFNDKLAAPLpEIPPDVVTECR 130
Cdd:pfam00615   1 SFDSLLEDQP-GRRLFRQFLESE-FSEENLEFWLACEEFKKADpDEERLKKAKEIYNEFLAPGSPKEI-NLDSDLREEIR 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 767929111  131 LGLKEEnPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQF 171
Cdd:pfam00615  78 ENLEKE-PTRDLFDEAQAEVYELMEKDSYPRFLKSPLYLRL 117

Catalytic domain of G protein-coupled Receptor Kinase 4-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of the GRK4-like group include GRK4, GRK5, GRK6, and similar GRKs. They contain an N-terminal RGS homology (RH) domain and a catalytic domain, but lack a G protein betagamma-subunit binding domain. They are localized to the plasma membrane through post-translational lipid modification or direct binding to PIP2. GRKs phosphorylate and regulate G protein-coupled receptors (GPCRs), the largest superfamily of cell surface receptors which regulate some part of nearly all physiological functions. Phosphorylated GPCRs bind to arrestins, which prevents further G protein signaling despite the presence of activating ligand. The GRK4-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767929111 186 TFRHYRVLGKGGFGEqspvgcavdgswkkqqpnvddteargpepeahdtifstfVCACQVRATGKMYACKKLQKKRIKKR 265
Cdd:cd05605    1 TFRQYRVLGKGGFGE---------------------------------------VCACQVRATGKMYACKKLEKKRIKKR 41

                         90       100
                 ....*....|....*....|.
gi 767929111 266 KGEAMALNEKRILEKVQSRFV 286
Cdd:cd05605   42 KGEAMALNEKQILEKVNSRFV 62

Catalytic domain of the Serine/Threonine Kinase, G protein-coupled Receptor Kinase 6; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GRK6 is widely expressed in many tissues and is expressed as multiple splice variants with different domain architectures. It is post-translationally palmitoylated and localized in the membrane. GRK6 plays important roles in the regulation of dopamine, M3 muscarinic, opioid, and chemokine receptor signaling. It also plays maladaptive roles in addiction and Parkinson's disease. GRK6-deficient mice exhibit altered dopamine receptor regulation, decreased lymphocyte chemotaxis, and increased acute inflammation and neutrophil chemotaxis. GRKs phosphorylate and regulate G protein-coupled receptors (GPCRs), the largest superfamily of cell surface receptors which regulate some part of nearly all physiological functions. Phosphorylated GPCRs bind to arrestins, which prevents further G protein signaling despite the presence of activating ligand. The GRK6 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767929111 186 TFRHYRVLGKGGFGEqspvgcavdgswkkqqpnvddteargpepeahdtifstfVCACQVRATGKMYACKKLQKKRIKKR 265
Cdd:cd05630    1 TFRQYRVLGKGGFGE---------------------------------------VCACQVRATGKMYACKKLEKKRIKKR 41

                         90       100
                 ....*....|....*....|.
gi 767929111 266 KGEAMALNEKRILEKVQSRFV 286
Cdd:cd05630   42 KGEAMALNEKQILEKVNSRFV 62

Catalytic domain of the Serine/Threonine Kinase, G protein-coupled Receptor Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GRKs phosphorylate and regulate G protein-coupled receptors (GPCRs), the largest superfamily of cell surface receptors, which regulate some part of nearly all physiological functions. Phosphorylated GPCRs bind to arrestins, which prevents further G protein signaling despite the presence of activating ligand. GRKs play important roles in the cardiovascular, immune, respiratory, skeletal, and nervous systems. They contain a central catalytic domain, flanked by N- and C-terminal extensions. The N-terminus contains an RGS (regulator of G protein signaling) homology (RH) domain and several motifs. The C-terminus diverges among different groups of GRKs. There are seven types of GRKs, named GRK1 to GRK7, which are subdivided into three main groups: visual (GRK1/7); beta-adrenergic receptor kinases (GRK2/3); and GRK4-like (GRK4/5/6). Expression of GRK2/3/5/6 is widespread while GRK1/4/7 show a limited tissue distribution. The substrate spectrum of the widely expressed GRKs partially overlaps. The GRK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 767929111 240 VCACQVRATGKMYACKKLQKKRIKKRKGEAMALNEKRILEKVQSRFV 286
Cdd:cd05577    9 VCACQVKATGKMYACKKLDKKRIKKKKGETMALNEKIILEKVSSPFI 55

Catalytic domain of the Serine/Threonine Kinase, G protein-coupled Receptor Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GRK1 (also called rhodopsin kinase) belongs to the visual group of GRKs and is expressed in retinal cells. It phosphorylates rhodopsin in rod cells, which leads to termination of the phototransduction cascade. Mutations in GRK1 are associated to a recessively inherited form of stationary nightblindness called Oguchi disease. GRKs phosphorylate and regulate G protein-coupled receptors (GPCRs), the largest superfamily of cell surface receptors, which regulate some part of nearly all physiological functions. Phosphorylated GPCRs bind to arrestins, which prevents further G protein signaling despite the presence of activating ligand. The GRK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767929111 187 FRHYRVLGKGGFGEqspvgcavdgswkkqqpnvddteargpepeahdtifstfVCACQVRATGKMYACKKLQKKRIKKRK 266
Cdd:cd05608    3 FLDFRVLGKGGFGE---------------------------------------VSACQMRATGKLYACKKLNKKRLKKRK 43

                         90       100
                 ....*....|....*....|
gi 767929111 267 GEAMALNEKRILEKVQSRFV 286
Cdd:cd05608   44 GYEGAMVEKRILAKVHSRFI 63

Regulator of G protein signaling domain (RGS) found in G protein-coupled receptor kinase 2 (GRK2) and G protein-coupled receptor kinase 3 (GRK3); The RGS domain is an essential part of the GRK2 (G protein-coupled receptor kinases 2) and the GRK3 proteins, which are members of the beta-adrenergic receptor kinases subfamily. GRK2 and GRK3 are ubiquitously expressed and can phosphorylate many different GPCR. The C-terminus of GRK2 and 3 contains a plekstrin homology domain (PH) with binding sites for the membrane phospholipid PIP2 and free G#? subunits. These specific interactions could help to maintain a membrane-bound population of GRK2 prior to the agonist-dependent overt GRK2 translocation. GRK2 and GRK3 are members of the GRK kinase family which includes three major subfamilies: the GRK4 subfamily (GRK4, GRK5 and GRK6), the rhodopsin kinase or visual GRK subfamily (GRK1 and GRK7), and the beta-adrenergic receptor kinases subfamily (GRK2/GRK3). The RGS domain of the GRKs 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. 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 767929111  60 QPIGRRLFRQFCDT-----KPTLKrhieFLDAVAEYEVAD-DEDRSDCGLSILDRFFNDKLAAPLPEIPPDVVTECRLGL 133
Cdd:cd08747   32 QKLGYLLFKDFCENvseepVPQLK----FYEEIKKYEKLDtEEERIKKAREIYDNYIMKELLSCSHPFSKSAVEHVQKHL 107

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 767929111 134 KEENPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQFLQWKWLE 178
Cdd:cd08747  108 SKKEVPVDLFEPYIEEICDSLRGDVFQKFLESDKFTRFCQWKNLE 152