Affinage

RIC8A

Chaperone Ric-8A · UniProt Q9NPQ8

Length
531 aa
Mass
59.7 kDa
Annotated
2026-04-28
52 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIC8A is a cytosolic guanine nucleotide exchange factor (GEF) and obligate biosynthetic chaperone for Gαi, Gαq, Gα12/13, and Gαs class heterotrimeric G protein α-subunits. Structurally, RIC8A adopts an armadillo/HEAT-repeat superhelical fold that engages the Gα C-terminus and switch regions; upon binding GDP-Gα, it induces large-scale α5-helix dislocation and Ras/helical domain separation to dismantle the nucleotide-binding pocket, stabilizing a nucleotide-free intermediate that is resolved by GTP loading (PMID:12509430, PMID:25605908, PMID:32103024, PMID:28008853). CK2-mediated phosphorylation of Ser435/Thr440 is essential for high-affinity Gα binding, GEF catalysis, and chaperone-mediated Gα folding, while NCS-1 acts as a Ca²⁺-sensitive negative regulator by trapping RIC8A in a conformation inaccessible to CK2 phosphorylation (PMID:29844055, PMID:38018500). Beyond its biochemical GEF/chaperone role, RIC8A prevents Gα ubiquitination and proteasomal degradation (PMID:23665327), recruits the LGN/NuMA/dynein cortical complex for mitotic spindle orientation and cytokinesis (PMID:20479129, PMID:24466196), and is required for integrin-mediated cell adhesion, neural crest migration, cerebellar foliation, and epithelial cystogenesis (PMID:23100420, PMID:23588098, PMID:28526238, PMID:28185378).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Genetic screens in C. elegans established that RIC-8 acts upstream of Gα signaling in two distinct contexts — Gαq-dependent neurotransmitter release and Gαo-dependent centrosome movements/spindle alignment — revealing it as a conserved regulator of heterotrimeric G protein pathways.

    Evidence Forward genetic epistasis screens and immunostaining in C. elegans neurons and early embryos

    PMID:10985349 PMID:11102364

    Open questions at the time
    • Biochemical mechanism of action on Gα was unknown
    • Whether RIC-8 acted as a GEF, scaffold, or chaperone was undetermined
  2. 2002 High

    Reconstituted biochemistry demonstrated that mammalian Ric-8A is a bona fide GEF for Gαq, Gαi1, and Gαo but not Gαs, defining its molecular activity as catalyzing GDP release and forming a stable nucleotide-free complex with Gα.

    Evidence In vitro GEF assays with purified recombinant proteins; yeast two-hybrid identification of Gα partners

    PMID:12509430

    Open questions at the time
    • Structural basis of the GEF mechanism was unknown
    • Whether Ric-8A had chaperone functions beyond GEF activity was untested
    • Relationship to GPCR-mediated GEF mechanism was unclear
  3. 2008 High

    Ric-8A was shown to displace the GPR/AGS3-type accessory protein from its complex with Gαi1-GDP through a transient ternary intermediate, establishing that Ric-8A can act on non-receptor Gα pools engaged by GoLoco-motif proteins.

    Evidence Gel filtration, isothermal titration calorimetry, and stopped-flow fluorescence with purified AGS3, Gαi1, and Ric-8A

    PMID:18541531

    Open questions at the time
    • Whether this reaction occurs at the mitotic cortex in cells was not shown
    • Kinetic parameters of the ternary complex were not fully resolved
  4. 2010 High

    Ric-8A was established as a mitotic regulator that localizes to the cell cortex, spindle poles, and midbody to recruit the LGN/NuMA/dynein complex via Gαi, thereby controlling spindle orientation; later work extended this to cytokinesis abscission via Vps34 PI3K.

    Evidence siRNA knockdown, pertussis toxin treatment, immunofluorescence, and live-cell imaging in HeLa and MDCK cells; FRET/FLIM biosensor for Ric-8A conformation at the midbody

    PMID:20479129 PMID:24466196

    Open questions at the time
    • Mechanism linking Ric-8A GEF activity to Vps34 regulation was indirect
    • Upstream signals controlling Ric-8A cortical localization during mitosis were unidentified
  5. 2011 High

    Biophysical characterization revealed that the nucleotide-free Gαi1 intermediate is conformationally dynamic and that Ric-8A stabilizes it, with the Gα C-terminus serving as a critical binding element — paralleling but mechanistically distinct from GPCR-mediated activation.

    Evidence TROSY-HSQC NMR, hydrogen-deuterium exchange, differential scanning calorimetry, and trypsinolysis on reconstituted complexes

    PMID:21853086

    Open questions at the time
    • Atomic-resolution structure of the Ric-8A:Gα complex was still lacking
    • Contribution of regions beyond the Gα C-terminus was undefined
  6. 2012 High

    Conditional knockout studies showed that Ric-8A is required in vivo for Bergmann glia basement-membrane adhesion during cerebellar foliation (phenocopying β1 integrin loss), and for neural crest cell migration and focal adhesion formation, linking Ric-8A to integrin signaling and tissue morphogenesis.

    Evidence Bergmann glia-specific conditional KO mice; Xenopus morpholino knockdown with chemotaxis and adhesion assays

    PMID:23100420 PMID:23588098

    Open questions at the time
    • Direct molecular link between Ric-8A GEF activity and integrin activation was not established
    • Which Gα subclass mediates the adhesion phenotype was not resolved
  7. 2015 High

    B-cell-specific Ric-8A ablation caused dramatic loss of Gαi, Gαq, and Gα13 proteins, establishing Ric-8A as an obligate biosynthetic chaperone whose loss leads to Gα degradation rather than merely reduced activation; separately, Ric-8A was shown to prevent Gα ubiquitination and proteasomal degradation.

    Evidence Conditional KO mice (mb1-cre) with Western blotting for Gα levels; co-IP and ubiquitination assays with proteasome inhibitor MG132

    PMID:23665327 PMID:26232433

    Open questions at the time
    • Identity of the E3 ubiquitin ligase targeting Gα in the absence of Ric-8A was unknown
    • Whether chaperone and GEF activities are mechanistically separable was unclear
  8. 2015 High

    DEER spectroscopy directly measured that Ric-8A induces up to 25 Å separation of the Gα helical and Ras-like domains, providing the first structural evidence for the mechanism of nucleotide release.

    Evidence Site-directed spin labeling and DEER spectroscopy on reconstituted Ric-8A:Gαi1 complex

    PMID:25605908

    Open questions at the time
    • Atomic-resolution structure was still lacking
    • Whether domain separation is the rate-limiting step for GDP release was untested
  9. 2018 High

    Identification of CK2-mediated phosphorylation at Ser435/Thr440 as essential for Ric-8A's GEF and chaperone activities resolved how a constitutive post-translational modification gates Ric-8A function, with conservation validated in C. elegans.

    Evidence Proteomics-based phosphosite identification; mutagenesis with in vitro GEF assays; C. elegans genomic mutation and pharmacological rescue

    PMID:29844055

    Open questions at the time
    • Whether other kinases regulate Ric-8A was unexplored
    • Structural effect of phosphorylation on the Ric-8A:Gα interface was unknown
  10. 2019 High

    Crystal structures of apo and Gα-peptide-bound Ric-8A revealed the armadillo/HEAT-repeat fold, mapped the Gα C-terminus binding groove, and showed that CK2 phosphorylation induces rotational rearrangement between ARM repeat groups, providing the structural framework for understanding GEF activity.

    Evidence X-ray crystallography (2.2 Å); SAXS; NMR chemical shift perturbation mapping; crosslinking-MS and MD simulations

    PMID:31155309 PMID:31300652 PMID:31624147

    Open questions at the time
    • Full-length Ric-8A:Gα complex structure at atomic resolution was still missing
    • How Ric-8A C-terminal tail organizes the GTP-binding site remained modeled rather than directly observed
  11. 2020 High

    Cryo-EM and crystal structures of the nanobody-stabilized nucleotide-free Ric-8A:Gαi1 complex at near-atomic resolution revealed the complete GEF mechanism: Ric-8A ejects the Gα α5-helix from its β-sheet core, dismantles the GDP-binding site, and engages the exposed β-sheet and switch II — a mechanism fundamentally distinct from GPCRs.

    Evidence Cryo-EM and X-ray crystallography of Ric-8A:Gαi1 complex stabilized by nanobody

    PMID:32103024

    Open questions at the time
    • Structure of Ric-8A bound to Gαq or Gα13 was not determined
    • Transition-state dynamics during GDP ejection were not captured
  12. 2023 High

    Structural and biochemical reconstitution showed that NCS-1 and Gα binding to Ric-8A are mutually exclusive: NCS-1 traps Ric-8A in a conformation inaccessible to CK2 phosphorylation, providing a Ca²⁺-sensitive toggle that regulates Ric-8A GEF output.

    Evidence X-ray crystallography of NCS-1:Ric-8A; NMR; GEF activity assays with titrated Ca²⁺ and CK2

    PMID:38018500

    Open questions at the time
    • Physiological contexts where Ca²⁺ fluctuations regulate Ric-8A through NCS-1 were not defined in mammalian cells
    • Whether NCS-1 also affects chaperone function independently of GEF activity was untested
  13. 2025 Medium

    Ric-8A was shown to directly control the nucleotide state of oncogenic GαqQ209L/P mutants; in RIC-8A KO cells these constitutively active mutants become sensitive to the GDP-dissociation inhibitor YM-254890, demonstrating that Ric-8A is required for maintaining the GTP-bound oncogenic state.

    Evidence CRISPR RIC-8A KO cells with rescue; BRET-based GRK2-RH reporter; pharmacological inhibition

    PMID:40118458

    Open questions at the time
    • Whether Ric-8A inhibition can be therapeutically exploited for GNAQ-driven cancers was not tested
    • Mechanism by which Ric-8A loss converts Q209L to a YM-sensitive state needs structural clarification

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how Ric-8A is recruited to the mitotic cortex, whether its GEF and chaperone activities are mechanistically separable, and whether structural insights can be leveraged for therapeutic targeting in GNAQ-driven malignancies.
  • Upstream signals controlling Ric-8A cortical recruitment during mitosis remain unknown
  • No structure of Ric-8A bound to Gαq or Gα13 exists
  • Separation-of-function mutations distinguishing GEF from chaperone activity have not been identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 10 GO:0044183 protein folding chaperone 4
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1640170 Cell Cycle 3
Partners
ADCY5GNA13GNAI1GNAQGPSM1GPSM2NCAM1NCS1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Ric-8A is a guanine nucleotide exchange factor (GEF) for a subset of Gα proteins (Gαq, Gαi1, Gαo but not Gαs). Mechanistically, Ric-8A interacts with GDP-bound Gα, stimulates GDP release, and forms a stable nucleotide-free transition-state complex that dissociates upon GTP binding. In vitro biochemical assay with purified recombinant Ric-8A; yeast two-hybrid identification of binding partners The Journal of biological chemistry High 12509430
2000 C. elegans RIC-8 (synembryn) functions upstream of or in conjunction with EGL-30 (Gαq) to regulate neurotransmitter secretion in neurons; RIC-8 is concentrated in the neuronal cytoplasm. Genetic epistasis (aldicarb-resistance screens, phorbol ester rescue, diacylglycerol kinase loss-of-function suppression); immunostaining for subcellular localization Neuron High 10985349
2000 C. elegans RIC-8 and GOA-1 (Gαo) regulate centrosome movements (posterior centrosome rocking, P1 centrosome flattening, mitotic spindle alignment, nuclear migration) during early embryogenesis; GOA-1 localizes to cell cortices and near centrosomes. Nomarski analysis of ric-8 and goa-1 loss-of-function mutants; genetic epistasis (dosage reduction); immunostaining of GOA-1 localization Genetics High 11102364
2003 Human synembryn (Ric-8A) interacts with Gαs and Gαq in yeast two-hybrid and in vitro pull-down assays, and translocates to the plasma membrane in response to isoproterenol (β-adrenergic) and carbachol (muscarinic) receptor stimulation. Yeast two-hybrid screen; in vitro pull-down; confocal live-cell imaging of translocation Journal of cellular physiology Medium 12652642
2004 C. elegans mutations rescuing ric-8 paralysis activate the Gαs pathway (Gαs, adenylyl cyclase, PKA), placing RIC-8 upstream of Gαq and Gαs pathways in the synaptic signaling network; neuronal (not muscle) Gαs activation is sufficient for rescue. Forward genetic screens; high-resolution mapping; sequence analysis; cell-specific transgene rescue; pharmacological assays Genetics High 15489510
2006 Ric-8A potentiates Gq-mediated signaling (ERK activation, intracellular calcium mobilization) downstream of GPCRs in intact cells; Ric-8A translocates to the cell membrane upon Gq-coupled receptor stimulation; its GEF activity for Gαq is required for this potentiation. siRNA knockdown; myristoylated membrane-targeted Ric-8A mutant expression; GEF activity assay; inhibitor YM-254890 Genes to cells Medium 16629901
2007 Ric-8A interacts directly with the N-terminus of type V adenylyl cyclase (AC5) and suppresses AC5 activity via a Gαi-mediated pathway; pertussis toxin or dominant-negative Gαi abolishes the suppressive effect. Pull-down assay; co-immunoprecipitation; co-localization in brain; dominant-negative Gαi expression; pertussis toxin treatment The Biochemical journal Medium 17593019
2008 Ric-8A catalyzes GDP release from the AGS3:Gαi1·GDP complex by forming a transient ternary complex; AGS3 is subsequently displaced, yielding a stable nucleotide-free Ric-8A·Gαi1 complex. AGS3 cannot reverse this reaction. Pulldown assays; gel filtration; isothermal titration calorimetry; stopped-flow fluorescence spectroscopy The Journal of biological chemistry High 18541531
2010 Ric-8A and Gαi co-operate to recruit LGN, NuMA, and dynein to the cell cortex, thereby orienting the mitotic spindle. Ric-8A localizes at the cell cortex, spindle poles, centromeres, central spindle, and midbody during mitosis; pertussis toxin blocks Ric-8A binding to Gαi and prevents GEF activity, impairing cortical complex assembly and spindle orientation. siRNA knockdown; pertussis toxin treatment; immunofluorescence; live-cell imaging of GFP-tubulin; co-localization studies Molecular and cellular biology High 20479129
2011 Ric-8A acts as a chaperone for the nucleotide-free state of Gαi1. The nucleotide-free Gαi1 is conformationally dynamic, and Ric-8A binding stabilizes it. The C-terminus of Gαi1 is a critical binding element for Ric-8A, suggesting mechanistic parallels with GPCR-mediated GEF activity. Trypsinolysis proteolysis assay; TROSY-HSQC NMR; hydrogen-deuterium exchange; differential scanning calorimetry PloS one High 21853086
2011 Ric-8A interacts directly with purified Gα13 in a nucleotide-dependent manner and is critical for coupling receptor tyrosine kinases to Gα13 to drive PDGF-induced dorsal ruffle turnover and cell migration; Ric-8A knockdown prevents translocation of Gα13 to the cell cortex. RNA interference; in vitro pull-down with purified proteins; live-cell imaging of dorsal ruffles; cell migration assay; GEF activity assay The Journal of biological chemistry Medium 21771786
2011 Ric-8A facilitates dissociation of the RGS14·Gαi1 complex and the Gαi1-dependent RGS14·α2A-adrenergic receptor complex after receptor activation, acting on the RGS14·Gαi1-GDP complex as a substrate. Live-cell bioluminescence resonance energy transfer (BRET); co-immunoprecipitation The Journal of biological chemistry Medium 21880739
2012 Ric-8A is required in Bergmann glia for their adhesion to the basement membrane during cerebellar foliation; ric-8a-deficient cerebellar glia show decreased affinity for basement membrane components and phenocopy β1 integrin deletion. Conditional knockout mice (Bergmann glia-specific); histological analysis; cell adhesion assay; genetic epistasis with β1 integrin deletion The Journal of neuroscience High 23100420
2012 NCAM180 interacts with Ric-8A and recruits it to the membrane/detergent-resistant membrane microdomains; NCAM180 forms a tripartite complex with Ric-8A and Gαs and potentiates β-adrenergic receptor-stimulated cAMP production in a Ric-8A-dependent manner. Yeast two-hybrid; co-immunoprecipitation; confocal microscopy; fractionation into detergent-resistant membranes; NCAM KO mouse brain comparison; cAMP measurement PloS one Medium 22384181
2013 Ric-8A stabilizes Gαi2 and Gαq by preventing their ubiquitination and proteasomal degradation; Ric-8A interaction via the Gα C-terminus is required for this stabilization. Co-immunoprecipitation; proteasome inhibitor MG132; ubiquitination assay; C-terminal truncation mutants Biochemical and biophysical research communications Medium 23665327
2013 Ric-8A is critical for cranial neural crest cell migration in Xenopus: knockdown impairs directional migration toward SDF-1, reduces cell spreading and focal adhesion formation; during migration Ric-8A localizes to the cell membrane. In vivo morpholino knockdown; NC transplantation assay; chemotaxis assay; immunofluorescence for focal adhesions; live-cell membrane localization imaging Developmental biology Medium 23588098
2013 Neuron-specific ablation of RIC8A in mice causes skeletal muscle atrophy, heart muscle hypoplasia, and misplaced sinoatrial node, demonstrating that RIC8A activity in neurons is essential for postnatal survival and neuromuscular maintenance. Conditional knockout (SynCre-driven Ric8a deletion); histological analysis; behavioral phenotyping PloS one Medium 23977396
2014 Ric-8A binds to NCS-1 (Frq2 in Drosophila); NCS-1 negatively regulates Ric-8A to control synapse number, while Ric-8A regulation of neurotransmitter release is independent of NCS-1 binding. The shared Frq2–Ric-8a–Gαs pathway diverges downstream for synapse number vs. release. Crystallographic data on Frq2; site-directed mutagenesis; co-immunoprecipitation; genetic epistasis in Drosophila Journal of cell science High 25074811
2014 Ric-8A and Gαi regulate cytokinesis abscission by controlling Vps34 phosphatidylinositol 3-kinase activity at the midbody; Ric-8A expression is post-transcriptionally regulated during the cell cycle, peaking at mitosis, and adopts a closed conformation during cytokinesis. FRET/FLIM biosensor for Ric-8A conformational changes; co-localization at midbody; siRNA knockdown; Vps34 activity assay; live-cell imaging of abscission timing PloS one Medium 24466196
2015 Ric-8A is an essential biosynthetic chaperone for Gα subunits (Gαi/q/13) in B lymphocytes; B-cell-specific loss of Ric-8A causes severe reduction of Gαi2/3, Gαq, and Gα13 proteins, impaired chemokine responses, abnormal trafficking, and loss of polarity during differentiation. Conditional knockout mice (mb1-cre); Western blotting for Gα levels; chemokine migration assays; histological analysis Journal of immunology High 26232433
2015 Ric-8A induces domain separation in Gαi1 with the helical and Ras-like nucleotide-binding domains pivoting apart by up to 25 Å, and causes structural plasticity in switch I and II regions in the Ric-8A:Gαi1 complex. Site-directed spin labeling (SDSL) combined with double electron-electron resonance (DEER) spectroscopy Proceedings of the National Academy of Sciences of the United States of America High 25605908
2015 Gα13 directly interacts with Ric-8A via Gα13's C-terminal guanine-ring interaction site; Gα13 stimulates tyrosine phosphorylation of Ric-8A (at Tyr-435, partially sensitive to Src-family kinase inhibitors), and promotes Ric-8A translocation to the plasma membrane. Ric-8A potentiates Gα13-mediated RhoA, Cdc42, and p38MAPK activation. Tandem affinity purification-mass spectrometry; serial deletion mapping; signaling assays; Src-family kinase inhibitors; subcellular fractionation Journal of molecular signaling Medium 27096001
2016 Ric-8A genetic ablation reduces oncogenic Gαq-Q209L protein levels below detectable amounts and completely abrogates GNAQ(Q209L)-driven melanoma tumorigenesis in mouse graft models, demonstrating Ric-8A is required for stability and oncogenic function of Gαq. Tamoxifen-inducible conditional Ric-8A knockout; cell graft tumorigenesis in immunocompromised mice; Western blotting for Gαq-Q209L levels Oncogenesis High 27348266
2016 HDX-MS shows that Ric-8A disrupts secondary structure of the Gα Ras-like domain around the nucleotide-binding site and destabilizes the interface between the Gαi1 Ras and helical domains, allowing domain separation and nucleotide release; alanine scanning identifies residues in a putative Gα-interaction site of Ric-8A critical for GEF activity; Ric-8A binds the C-terminus of Gα (as do GPCRs) but also interacts with Switches I and II. Hydrogen-Deuterium Exchange-Mass Spectrometry (HDX-MS); alanine scanning mutagenesis; GEF activity assays eLife High 28008853
2017 Ric-8A crystal structure (NCS-1/FD44 complex) reveals that small molecule FD44 stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1, preventing Ric-8A binding; disrupting the NCS-1/Ric-8A complex restores normal synapse number and associative learning in a Drosophila FXS model. X-ray crystallography of NCS-1 bound to FD44; virtual screening; in vivo Drosophila FXS model rescue Proceedings of the National Academy of Sciences of the United States of America High 28119500
2017 Ric-8A is required for mitotic spindle orientation and cystogenesis in MDCK epithelial cells, acting through Gαi and LGN; Ric-8A knockdown delays tight junction assembly in a mitosis-independent manner and impairs cortical delivery of Gαi and the apical membrane protein gp135. 3D culture cystogenesis assay; siRNA knockdown; immunofluorescence; ADP-ribosylated Gαi mutant rescue experiments Genes to cells Medium 28185378
2017 RIC8A is required for actin cytoskeleton organization, cell spreading, stress fiber and focal adhesion formation, β1 integrin activation, and integrin-mediated cell migration; Ric8a-/- cells attach to ECM but cannot spread correctly. Ric8a-/- mouse embryonic stem cells and fibroblasts; actin staining; focal adhesion immunofluorescence; integrin activation assay; migration assay Experimental cell research Medium 28526238
2018 Ric-8A is constitutively phosphorylated at five CK2 sites; phosphorylation of Ser435 and Thr440 (rat; Ser436/Thr441 in human) by CK2 is required for high-affinity Gα binding, efficient GEF activity, and Gα subunit folding/chaperoning. Mutation of homologous residues in C. elegans ric-8 causes characteristic reduction-of-function phenotypes rescued by Gq pathway activation. Proteomics; Western blotting; mutational analysis; in vitro GEF assay; C. elegans genomic mutation; pharmacological rescue Science signaling High 29844055
2019 Crystal structures of Ric-8A (apo and in complex with Gα C-terminal fragment) reveal an armadillo-fold core domain and a flexible C-terminal tail; the Gα C-terminus binds a conserved concave surface of the armadillo domain; the Ric-8A C-terminal tail is critical for stability and GEF function; crosslinking-MS and MD simulations suggest the C-terminal tail helps organize the GTP-binding site of Gα. X-ray crystallography; crosslinking mass spectrometry; molecular dynamics simulations; biochemical Gα binding and GEF assays Nature communications High 31300652
2019 Crystal structure of Ric-8A residues 1-452 (phosphorylated at Ser435/Thr440) reveals an armadillo/HEAT repeat superhelical fold; phosphorylation induces relative rotation between ARM repeat groups; NMR chemical shift perturbations map Ric-8A interaction to Gαi1 C-terminus and nucleotide-binding residues. X-ray crystallography (2.2 Å); SAXS with normal mode modeling; 2D 1H-15N TROSY NMR Structure High 31155309
2019 SAXS and steered MD modeling of Ric-8A/miniGαi complex reveals large-scale rearrangement of the Gα α5-helix away from its β-sheet core upon Ric-8A binding, severely disrupting the GDP-binding site; the Ric-8A C-terminal tail interacts with the effector surface of Gα. Small-angle X-ray scattering (SAXS); steered molecular dynamics simulations The Journal of biological chemistry Medium 31624147
2020 Cryo-EM and X-ray structures of the nanobody-stabilized nucleotide-free Gαi1 bound to phosphorylated Ric-8A reveal: (1) Ric-8A engages Gα at multiple interfaces stabilized by CK2 phosphorylation in a connecting segment; (2) the Gα C-terminus is ejected from its β-sheet core, dismantling the GDP-binding site; (3) Ric-8A binds the exposed Gα β-sheet and switch II to stabilize the nucleotide-free state; the GEF mechanism is distinct from GPCRs. Cryo-electron microscopy; X-ray crystallography; nanobody stabilization Nature communications High 32103024
2021 circPDE4B acts as a scaffold to promote RIC8A degradation through proteasomal degradation, facilitated by the MID1 E3 ubiquitin ligase; ubiquitination of RIC8A at K415 abrogates this degradation. The circPDE4B-RIC8A axis regulates downstream p38 MAPK signaling in chondrocytes. RNA pull-down-mass spectrometry; immunoprecipitation; GST pull-down; RNA immunoprecipitation; site-directed mutagenesis (K415); AAV delivery in OA mouse model Annals of the rheumatic diseases Medium 34039624
2023 NCS-1 and Gα binding to Ric-8A are mutually exclusive. NCS-1 induces a structural rearrangement in Ric-8A that traps it in a conformation inaccessible to CK2 phosphorylation, blocking GEF activity toward Gα. Increasing Ca2+ concentration restores Ric-8A GEF activity by relieving NCS-1 inhibition. Reconstitution of NCS-1/Ric-8A complexes; GEF activity assays; NMR; X-ray crystallography; phosphorylation assays with CK2 eLife High 38018500
2025 Ric-8A enhances the activation of constitutively active αqQ209L/P mutants by promoting GTP-bound states; in RIC-8A KO cells, myristoylated αqQL/P mutants become YM-254890-sensitive (GDP-dissociation inhibitor sensitive), an effect reversed by Ric-8A re-introduction, demonstrating Ric-8A directly controls the nucleotide state of oncogenic Gαq. CRISPR RIC-8A KO cells; signaling assays; BRET with GRK2-RH domain reporter; pharmacological YM-254890 inhibition; pull-down assays The Journal of biological chemistry Medium 40118458

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Mammalian Ric-8A (synembryn) is a heterotrimeric Galpha protein guanine nucleotide exchange factor. The Journal of biological chemistry 259 12509430
2010 Ric-8A and Gi alpha recruit LGN, NuMA, and dynein to the cell cortex to help orient the mitotic spindle. Molecular and cellular biology 139 20479129
2008 Insertional mutagenesis by the Tol2 transposon-mediated enhancer trap approach generated mutations in two developmental genes: tcf7 and synembryn-like. Development (Cambridge, England) 139 18065431
2000 RIC-8 (Synembryn): a novel conserved protein that is required for G(q)alpha signaling in the C. elegans nervous system. Neuron 118 10985349
2000 A role for RIC-8 (Synembryn) and GOA-1 (G(o)alpha) in regulating a subset of centrosome movements during early embryogenesis in Caenorhabditis elegans. Genetics 106 11102364
2004 Mutations that rescue the paralysis of Caenorhabditis elegans ric-8 (synembryn) mutants activate the G alpha(s) pathway and define a third major branch of the synaptic signaling network. Genetics 99 15489510
2021 circPDE4B prevents articular cartilage degeneration and promotes repair by acting as a scaffold for RIC8A and MID1. Annals of the rheumatic diseases 88 34039624
2008 Ric-8A catalyzes guanine nucleotide exchange on G alphai1 bound to the GPR/GoLoco exchange inhibitor AGS3. The Journal of biological chemistry 58 18541531
2003 Human brain synembryn interacts with Gsalpha and Gqalpha and is translocated to the plasma membrane in response to isoproterenol and carbachol. Journal of cellular physiology 50 12652642
2011 The nucleotide exchange factor Ric-8A is a chaperone for the conformationally dynamic nucleotide-free state of Gαi1. PloS one 48 21853086
2006 Ric-8A potentiates Gq-mediated signal transduction by acting downstream of G protein-coupled receptor in intact cells. Genes to cells : devoted to molecular & cellular mechanisms 44 16629901
2017 Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome. Proceedings of the National Academy of Sciences of the United States of America 35 28119500
2011 Resistance to inhibitors of cholinesterase-8A (Ric-8A) is critical for growth factor receptor-induced actin cytoskeletal reorganization. The Journal of biological chemistry 29 21771786
2014 The guanine-exchange factor Ric8a binds to the Ca²⁺ sensor NCS-1 to regulate synapse number and neurotransmitter release. Journal of cell science 28 25074811
2011 G protein-coupled receptors and resistance to inhibitors of cholinesterase-8A (Ric-8A) both regulate the regulator of g protein signaling 14 RGS14·Gαi1 complex in live cells. The Journal of biological chemistry 28 21880739
2009 Ric-8A, a Galpha protein guanine nucleotide exchange factor potentiates taste receptor signaling. Frontiers in cellular neuroscience 26 19847316
2016 Ric-8A, a G protein chaperone with nucleotide exchange activity induces long-range secondary structure changes in Gα. eLife 25 28008853
2012 Ric-8a, a guanine nucleotide exchange factor for heterotrimeric G proteins, regulates bergmann glia-basement membrane adhesion during cerebellar foliation. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 23100420
2003 Expression of ric-8 (synembryn) gene in the nervous system of developing and adult mouse. Gene expression patterns : GEP 24 12971991
2019 Structural underpinnings of Ric8A function as a G-protein α-subunit chaperone and guanine-nucleotide exchange factor. Nature communications 23 31300652
2020 Structure of the G protein chaperone and guanine nucleotide exchange factor Ric-8A bound to Gαi1. Nature communications 22 32103024
2009 Novel regulation of adenylyl cyclases by direct protein-protein interactions: insights from snapin and ric8a. Neuro-Signals 22 19202347
2007 Regulation of type V adenylate cyclase by Ric8a, a guanine nucleotide exchange factor. The Biochemical journal 22 17593019
2004 Purification and functional analysis of Ric-8A: a guanine nucleotide exchange factor for G-protein alpha subunits. Methods in enzymology 21 15488189
2015 B Lymphocyte-Specific Loss of Ric-8A Results in a Gα Protein Deficit and Severe Humoral Immunodeficiency. Journal of immunology (Baltimore, Md. : 1950) 20 26232433
2019 Structure, Function, and Dynamics of the Gα Binding Domain of Ric-8A. Structure (London, England : 1993) 19 31155309
2014 A Ric8/synembryn homolog promotes Gpa1 and Gpa2 activation to respectively regulate cyclic AMP and pheromone signaling in Cryptococcus neoformans. Eukaryotic cell 18 25084863
2015 The guanine nucleotide exchange factor Ric-8A induces domain separation and Ras domain plasticity in Gαi1. Proceedings of the National Academy of Sciences of the United States of America 17 25605908
2014 Resistance to inhibitors of cholinesterase (Ric)-8A and Gαi contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity. PloS one 17 24466196
2013 Ric-8A, a guanine nucleotide exchange factor for heterotrimeric G proteins, is critical for cranial neural crest cell migration. Developmental biology 17 23588098
2013 Ubiquitination of the heterotrimeric G protein α subunits Gαi2 and Gαq is prevented by the guanine nucleotide exchange factor Ric-8A. Biochemical and biophysical research communications 17 23665327
2018 Dual phosphorylation of Ric-8A enhances its ability to mediate G protein α subunit folding and to stimulate guanine nucleotide exchange. Science signaling 14 29844055
2016 Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQ(Q209L)-driven melanoma. Oncogenesis 14 27348266
2017 Ric-8A, an activator protein of Gαi, controls mammalian epithelial cell polarity for tight junction assembly and cystogenesis. Genes to cells : devoted to molecular & cellular mechanisms 12 28185378
2013 Ablation of RIC8A function in mouse neurons leads to a severe neuromuscular phenotype and postnatal death. PloS one 11 23977396
2021 Proteomic and molecular evidences of Il1rl2, Ric8a, Krt18 and Hsp90b1 modulation during experimental hepatic fibrosis and pomegranate supplementation. International journal of biological macromolecules 8 34174316
2018 Deciphering the Inhibition of the Neuronal Calcium Sensor 1 and the Guanine Exchange Factor Ric8a with a Small Phenothiazine Molecule for the Rational Generation of Therapeutic Synapse Function Regulators. Journal of medicinal chemistry 8 29966094
2016 ARMS/Kidins220 and synembryn-B levels regulate NGF-mediated secretion. Journal of cell science 8 26966186
2009 Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line. BMC medical genomics 8 19432969
2020 Ric-8A, a GEF, and a Chaperone for G Protein α-Subunits: Evidence for the Two-Faced Interface. BioEssays : news and reviews in molecular, cellular and developmental biology 6 31967346
2019 Large-scale conformational rearrangement of the α5-helix of Gα subunits in complex with the guanine nucleotide exchange factor Ric8A. The Journal of biological chemistry 6 31624147
2012 NCAM180 regulates Ric8A membrane localization and potentiates β-adrenergic response. PloS one 6 22384181
2018 Ric-8A, a GEF for heterotrimeric G-proteins, controls cranial neural crest cell polarity during migration. Mechanisms of development 5 30016646
2015 Deletion of RIC8A in neural precursor cells leads to altered neurogenesis and neonatal lethality of mouse. Developmental neurobiology 5 25641781
2015 Gα13 Stimulates the Tyrosine Phosphorylation of Ric-8A. Journal of molecular signaling 5 27096001
2017 RIC8A is essential for the organisation of actin cytoskeleton and cell-matrix interaction. Experimental cell research 4 28526238
2023 The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the Gα chaperone and GEF Ric-8A. eLife 3 38018500
2022 The inhibition of NCS-1 binding to Ric8a rescues fragile X syndrome mice model phenotypes. Frontiers in neuroscience 3 36466176
2018 Production of Phosphorylated Ric-8A proteins using protein kinase CK2. Protein expression and purification 3 30290220
2025 The guanine nucleotide exchange factor Ric-8A regulates the sensitivity of constitutively active Gαq to the inhibitor YM-254890. The Journal of biological chemistry 1 40118458
2018 Targeted deletion of RIC8A in mouse neural precursor cells interferes with the development of the brain, eyes, and muscles. Developmental neurobiology 1 29380551
2016 Nanosecond Dynamics of Gαi1 Bound to Nucleotides or Ric-8A, a Gα Chaperone with GEF Activity. Biophysical journal 1 27558716