Affinage

RGS11

Regulator of G-protein signaling 11 · UniProt O94810

Length
467 aa
Mass
52.9 kDa
Annotated
2026-04-28
12 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS11 is an R7-family regulator of G-protein signaling that accelerates GTP hydrolysis on Gαi/o-class subunits to terminate G-protein-coupled receptor signaling, with critical roles in retinal ON-bipolar cell light responses. Through its GGL domain, RGS11 obligatorily heterodimerizes with Gβ5, and the resulting Gβ5/RGS11 complex selectively acts as a GAP for Gαo, exhibiting higher maximal catalytic activity than other R7 family members (PMID:9789084, PMID:12531899). In retinal ON-bipolar cells, RGS11 assembles into a trimeric complex with Gβ5S and the membrane anchor R9AP at dendritic tips through direct association with mGluR6; R9AP allosterically potentiates GAP activity, stabilizes the complex against proteolysis, and together with RGS7 the complex sets the sensitivity and onset kinetics of the light-evoked depolarization by controlling Gαo deactivation upstream of TRPM1 channels (PMID:19625520, PMID:20007977, PMID:22547806). In cardiomyocytes, RGS11 forms a complex with CaMKII and ATF3 to counteract oxidative stress-driven apoptosis, and cardiac-specific overexpression protects against doxorubicin-induced cardiotoxicity (PMID:36228439).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    The discovery that RGS11 contains a GGL domain mediating specific heterodimerization with Gβ5 and conferring selective GAP activity toward Gαo established RGS11 as a Gβ5-dependent, Gi/o-selective GTPase-activating protein, distinguishing it from simple RGS-box GAPs.

    Evidence Coexpression with multiple Gβ subunits, co-immunoprecipitation, and reconstituted GTPase assays in mammalian cells

    PMID:9789084

    Open questions at the time
    • Structural basis of GGL–Gβ5 interaction not resolved
    • In vivo biological context of GAP activity unknown
  2. 1999 High

    Mutagenesis of a conserved GGL-domain residue (Phe-61→Trp) revealed that a single amino acid governs heterodimer stability with Gβ5, establishing that GGL–Gβ5 pairing is structurally analogous to conventional Gβγ interactions.

    Evidence Site-directed mutagenesis with direct binding assays and structural predictions

    PMID:10339615

    Open questions at the time
    • No crystal structure of GGL–Gβ5 interface available for RGS11 specifically
    • Functional consequence of altered dimer stability not tested in vivo
  3. 2003 High

    Quantitative comparison of purified R7 family GAPs showed that Gβ5/RGS11 has the highest maximal catalytic activity toward Gαo among R7 members and can be competitively inhibited by Gβ5/RGS7 and Gβ5/RGS9, defining a hierarchy and competitive interplay among R7 GAPs.

    Evidence Steady-state GTPase assays with purified Sf9-expressed proteins reconstituted into proteoliposomes containing muscarinic receptor–G-protein heterotrimers

    PMID:12531899

    Open questions at the time
    • Physiological relevance of inter-R7 competition not tested in native tissue
    • Membrane-anchor contributions not included in this reconstitution
  4. 2009 High

    Identification of the obligatory RGS11–Gβ5S–R9AP trimeric complex at ON-bipolar cell dendritic tips, and its direct association with mGluR6, placed RGS11 at the precise site of signal transduction in the retinal ON pathway and explained how postsynaptic targeting and proteolytic stabilization are achieved.

    Evidence Co-immunoprecipitation, immunofluorescence in wild-type and knockout mouse retinae, electrophysiological recordings

    PMID:19625520

    Open questions at the time
    • Molecular interface between RGS11 complex and mGluR6 not structurally defined
    • Relative contribution of RGS11 vs. RGS7 to ON-bipolar signaling not resolved
  5. 2009 High

    Demonstration that R9AP allosterically potentiates the GAP activity of RGS11·Gβ5 toward Gαo, and that R9AP is required for functional GTPase acceleration in reconstituted mGluR6–Gαo signaling, revealed R9AP as an essential catalytic cofactor rather than a passive membrane anchor.

    Evidence Single-turnover GTPase assays with membrane-anchored proteins; Xenopus oocyte electrophysiological reconstitution of mGluR6–Gαo pathway

    PMID:20007977

    Open questions at the time
    • Structural mechanism of allosteric potentiation unknown
    • Whether R7BP provides analogous allosteric activation not established
  6. 2009 Medium

    Binding of Gβ5-free RGS11 to R7BP with higher affinity than to Gαo suggested an alternative membrane-anchoring partner for RGS11 outside the retina, though the physiological significance of Gβ5-independent RGS11 remains uncertain.

    Evidence Equilibrium binding assays and GTPase assays with purified E. coli–expressed Gβ5-free RGS11

    PMID:19497306

    Open questions at the time
    • Gβ5-free RGS11 not demonstrated in vivo
    • Single-lab finding not independently confirmed
    • Functional relevance of R7BP–RGS11 interaction in native tissue unknown
  7. 2010 High

    Genetic deletion of R9AP selectively depleted RGS11 (but not RGS7) from ON-bipolar dendrites and delayed the ERG b-wave, establishing that R9AP is required in vivo for RGS11 complex stability and that RGS11 contributes to the speed of the initial ON response.

    Evidence R9AP knockout mice with immunofluorescence quantification and electroretinography

    PMID:20100392

    Open questions at the time
    • Contribution of RGS11 loss versus other R9AP-dependent proteins to ERG phenotype not fully dissected
    • Compensatory upregulation of other GAPs not examined
  8. 2012 High

    Double knockout of RGS7 and RGS11 severely reduced and slowed ON-bipolar light responses, demonstrating that these two proteins together constitute the dominant GAP machinery controlling Gαo deactivation and TRPM1 channel gating in rod ON-bipolar cells.

    Evidence RGS7/RGS11 double-knockout mice with ERG and single-cell patch-clamp recordings

    PMID:22547806

    Open questions at the time
    • Individual relative contributions of RGS11 vs. RGS7 not quantitatively separated in this study
    • Role in cone ON-bipolar cells not fully resolved
  9. 2022 Medium

    Discovery that RGS11 directly complexes with CaMKII and ATF3 in cardiomyocytes to suppress oxidative stress and apoptosis expanded RGS11 function beyond retinal GAP activity to a cardioprotective role, with CaMKII inhibition rescuing the RGS11-knockdown phenotype.

    Evidence Co-immunoprecipitation of RGS11–CaMKII complex, cardiac-specific overexpression and shRNA knockdown in mice, CaMKII inhibitor rescue, doxorubicin cardiotoxicity model

    PMID:36228439

    Open questions at the time
    • Single-lab study; independent replication needed
    • Whether RGS11 GAP activity is involved in the cardiac phenotype not tested
    • Mechanism by which RGS11 suppresses CaMKII-driven oxidative stress not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for R9AP allosteric potentiation of RGS11 GAP activity, the precise molecular interface between the RGS11 complex and mGluR6, and the mechanism by which RGS11 inhibits CaMKII/ATF3-mediated apoptosis in cardiomyocytes remain unresolved.
  • No high-resolution structure of the RGS11–Gβ5–R9AP–mGluR6 complex
  • GAP-dependent versus GAP-independent functions of RGS11 in the heart not distinguished
  • Whether RGS11 participates in signaling outside retina and heart is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 3
Partners
ATF3CAMK2AGNAO1GNB5GRM6RGS9AP
Complex memberships
RGS11–Gβ5S–R9AP

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RGS11 contains a G protein gamma subunit-like (GGL) domain that mediates specific interaction with Gβ5 subunits; the resulting Gβ5/RGS11 heterodimer acts as a GTPase-activating protein (GAP) selectively on Gαo. Coexpression of RGS11 with different Gβ subunits in cells (co-immunoprecipitation), GTPase assays Proceedings of the National Academy of Sciences of the United States of America High 9789084
1999 The GGL domain of RGS11 interacts with Gβ5 in a manner analogous to conventional Gβ/Gγ pairing; mutation of the conserved Phe-61 residue (equivalent position in Gγ2) to tryptophan (the residue present in all GGL domains) increases Gβ5 heterodimer stability, establishing this residue as critical for GGL/Gβ5 association. GGL domain mutagenesis, Gβ binding assays, coiled-coil/alpha-helix structural predictions Proceedings of the National Academy of Sciences of the United States of America High 10339615
2003 Purified Gβ5/RGS11 heterodimer stimulates GTPase activity of Gi-family Gα subunits (Gαo, Gαi1, Gαi2, Gαi3) but not Gαq or Gα11; Gβ5/RGS11 exhibits higher maximal GAP activity (2–4 fold) than Gβ5/RGS7 or Gβ5/RGS9 toward Gαo, and can be competitively inhibited by Gβ5/RGS7 and Gβ5/RGS9. Steady-state and concentration-effect GTPase assays using purified Sf9-derived R7 proteins reconstituted into proteoliposomes with muscarinic receptor-coupled G-protein heterotrimers The Journal of biological chemistry High 12531899
2009 RGS11 forms an obligatory trimeric complex with the short splice isoform of Gβ5 (Gβ5S) and the RGS9 anchor protein (R9AP); this complex is exclusively localized to dendritic tips of ON-bipolar cells through direct association with mGluR6; both R9AP and mGluR6 association contribute to proteolytic stabilization of the complex, whereas postsynaptic targeting is not determined by R9AP. Co-immunoprecipitation, immunofluorescence colocalization, genetic knockout mice, electrophysiological recordings (single-cell light responses) The Journal of neuroscience : the official journal of the Society for Neuroscience High 19625520
2009 R9AP co-localizes RGS11·Gβ5 and Gαo on the membrane and allosterically potentiates GAP activity of the RGS11·Gβ5 complex toward Gαo; in Xenopus oocyte reconstitution of mGluR6–Gαo signaling, RGS11·Gβ5-mediated GTPase acceleration requires co-expression of R9AP. Single-turnover GTPase assays with membrane-anchored proteins, Xenopus oocyte electrophysiological reconstitution The Journal of biological chemistry High 20007977
2010 Genetic deletion of R9AP results in a marked reduction in RGS11 and Gβ5 protein levels in ON-bipolar cell dendrites (but not RGS7 levels), demonstrating that R9AP is required for proteolytic stability of the RGS11–Gβ5 complex in vivo; R9AP deletion delays and enlarges the ERG b-wave, indicating the RGS11–Gβ5–R9AP complex accelerates the initial ON-bipolar cell light response. R9AP knockout mice, immunofluorescence, ERG recordings Visual neuroscience High 20100392
2012 RGS11 and RGS7 together are the dominant GAPs in the mGluR6 pathway of rod ON-bipolar cells; concurrent genetic elimination of both RGS7 and RGS11 severely reduces the magnitude and dramatically slows the onset of light-evoked responses, biasing TRPM1 channels to a closed state due to persistently high Gαo activity. RGS7/RGS11 double-knockout mice, electroretinography, single-cell electrophysiological recordings Proceedings of the National Academy of Sciences of the United States of America High 22547806
2009 Gβ5-free recombinant RGS11 binds R7BP (RGS7 family binding protein) with higher affinity (KD ~308 nM) than Gαoa (KD ~904 nM) and stimulates GTPase activity of Gαoa; a novel interaction between Gαoa and R7BP (KD ~592 nM) was also identified. Purified recombinant Gβ5-free RGS11 expressed in E. coli, equilibrium binding assays, GTPase activity assays Biochemical and biophysical research communications Medium 19497306
2022 RGS11 forms a direct complex with the apoptotic kinase CaMKII and stress-responsive transcription factor ATF3 in cardiomyocytes; RGS11 counterbalances CaMKII/ATF3-driven oxidative stress, mitochondrial dysfunction, and apoptosis; cardiac-specific overexpression of RGS11 decreases doxorubicin-induced fibrosis, hypertrophy, and cell loss, while RGS11 knockdown promotes cardiac fibrosis that is largely prevented by CaMKII inhibition. Co-immunoprecipitation (RGS11–CaMKII complex), cardiac-specific overexpression and shRNA knockdown in mice, CaMKII inhibitor rescue experiment, doxorubicin cardiotoxicity model Redox biology Medium 36228439

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A G protein gamma subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gbeta5 subunits. Proceedings of the National Academy of Sciences of the United States of America 225 9789084
2003 RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity. The Journal of biological chemistry 126 12531899
1999 Fidelity of G protein beta-subunit association by the G protein gamma-subunit-like domains of RGS6, RGS7, and RGS11. Proceedings of the National Academy of Sciences of the United States of America 101 10339615
2009 Retina-specific GTPase accelerator RGS11/G beta 5S/R9AP is a constitutive heterotrimer selectively targeted to mGluR6 in ON-bipolar neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 19625520
2012 Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proceedings of the National Academy of Sciences of the United States of America 69 22547806
2009 Membrane anchor R9AP potentiates GTPase-accelerating protein activity of RGS11 x Gbeta5 complex and accelerates inactivation of the mGluR6-G(o) signaling. The Journal of biological chemistry 21 20007977
2010 R9AP stabilizes RGS11-G beta5 and accelerates the early light response of ON-bipolar cells. Visual neuroscience 20 20100392
2022 RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis. Redox biology 17 36228439
2019 Diagnosing the RGS11 Lung Cancer Biomarker: The Integration of Competitive Immunoassay and Isothermal Nucleic Acid Exponential Amplification Reaction. Analytical chemistry 8 30701963
2001 Identification and characterization of alternatively spliced murine Rgs11 isoforms: genomic structure and gene analysis. Cytogenetics and cell genetics 7 11856884
2023 Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 37440271
2009 RGS11 interacts preferentially with R7BP over Galpha(oa)--characterization of Gbeta5-free RGS11. Biochemical and biophysical research communications 3 19497306