Affinage

RIC8A

Chaperone Ric-8A · UniProt Q9NPQ8

Length
531 aa
Mass
59.7 kDa
Annotated
2026-06-10
52 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIC8A (Ric-8A/synembryn) is a cytosolic guanine nucleotide exchange factor and folding chaperone for Gαi/q/12/13-class heterotrimeric G protein α subunits, functioning as a non-receptor amplifier of G protein signaling downstream of GPCRs and receptor tyrosine kinases (PMID:12509430, PMID:16629901, PMID:21771786). Biochemically, Ric-8A binds GDP-bound Gα (but not Gαs), stimulates GDP release, and forms a stable nucleotide-free transition-state complex that dissociates upon GTP binding (PMID:12509430); structural work establishes that Ric-8A engages the Gα C-terminus, switch regions, and domain interface via the concave surface of an armadillo/HEAT-repeat fold, driving large-scale separation of the Ras-like and helical domains and ejection of the α5-helix to dismantle the GDP-binding site — a mechanism distinct from GPCR-mediated exchange (PMID:25605908, PMID:28008853, PMID:31300652, PMID:32103024). Beyond catalysis, Ric-8A acts as a chaperone that stabilizes the conformationally dynamic nucleotide-free state and prevents polyubiquitination and proteasomal degradation of nascent Gα, such that loss of Ric-8A collapses cellular Gαi/q/13 protein levels (PMID:21853086, PMID:23665327, PMID:26232433). Its GEF and chaperone activities are potentiated by constitutive CK2 phosphorylation at Ser435/Thr440 and switched off by Ca2+-regulated NCS-1 binding, which traps Ric-8A in a phosphorylation-inaccessible conformation mutually exclusive with Gα engagement (PMID:29844055, PMID:38018500). Through these activities Ric-8A is required for mitotic spindle orientation via cortical LGN/NuMA/dynein recruitment, cytokinetic abscission via Vps34, actin cytoskeleton organization and β1-integrin activation, neural crest and B-cell migration, cerebellar foliation, and epithelial polarity (PMID:20479129, PMID:23100420, PMID:24466196, PMID:26232433, PMID:28185378, PMID:28526238). Its chaperone function is also required for oncogenic GNAQ(Q209L)-driven melanoma, where Ric-8A ablation eliminates the mutant Gαq protein and abrogates tumorigenesis (PMID:27348266).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2000 High

    Established RIC-8 as a genetic component of the heterotrimeric G protein signaling network in vivo before its biochemical activity was known, placing it in the Gαo/Gαq pathway controlling neurotransmitter release and in centrosome/spindle positioning.

    Evidence Forward genetic screens, epistasis, and immunostaining in C. elegans

    PMID:10985349 PMID:11102364

    Open questions at the time
    • Molecular activity of RIC-8 protein undefined
    • Direct biochemical relationship to Gα subunits not established
  2. 2002 High

    Defined the core biochemical activity: Ric-8A is a GEF for a selective subset of Gα subunits that stimulates GDP release and forms a nucleotide-free intermediate, resolving how it amplifies G protein signaling.

    Evidence Y2H, recombinant protein purification, and in vitro nucleotide exchange assays

    PMID:12509430

    Open questions at the time
    • Structural basis of nucleotide release unknown
    • Excludes Gαs but mechanism of selectivity unexplained
  3. 2003 Medium

    Linked Ric-8A activity to receptor stimulation by showing GPCR agonist-induced plasma membrane translocation, connecting cytosolic GEF activity to receptor activation in cells.

    Evidence Y2H, in vitro pulldown, live-cell confocal translocation in response to carbachol/isoproterenol

    PMID:12652642

    Open questions at the time
    • Reported Gαs interaction conflicts with in vitro GEF selectivity
    • Mechanism of agonist-driven translocation not defined
  4. 2004 High

    Broadened the in vivo signaling scope by linking RIC-8 to the Gαs/adenylyl cyclase/PKA branch, indicating it integrates across multiple Gα pathways in neurons.

    Evidence Forward genetics, mapping, and cell-specific rescue in C. elegans

    PMID:15489510

    Open questions at the time
    • Whether Gαs effects are direct or indirect unresolved
    • Biochemical basis for Gαs-branch genetics unclear
  5. 2006 Medium

    Demonstrated in intact cells that Ric-8A amplifies Gq-dependent ERK and calcium signaling downstream of GPCRs, confirming functional GEF amplifier activity in a cellular context.

    Evidence siRNA knockdown, membrane-targeted overexpression, ERK/calcium assays and Gq inhibitor in 293T cells

    PMID:16629901

    Open questions at the time
    • Single cell system
    • Endogenous receptor coupling not fully delineated
  6. 2007 Medium

    Connected Ric-8A to effector regulation by showing it suppresses adenylyl cyclase type 5 through a Gαi-mediated mechanism, extending its role to downstream effector output.

    Evidence Pulldown, co-IP, brain co-localization, AC5 activity assays with pertussis toxin/dominant-negative Gαi

    PMID:17593019

    Open questions at the time
    • Direct vs Gαi-bridged AC5 contact ambiguous
    • Single lab
  7. 2008 High

    Defined how Ric-8A overrides GDI regulators: it catalyzes GDP release from AGS3:Gαi1·GDP via a ternary intermediate, ensuring unidirectional Gαi activation that cannot be reversed by AGS3.

    Evidence Pulldown, gel filtration, ITC, stopped-flow fluorescence kinetics

    PMID:18541531

    Open questions at the time
    • Cellular relevance of AGS3 displacement not tested in vivo
  8. 2010 High

    Established a cell-biological function: Ric-8A and Gαi orient the mitotic spindle by recruiting cortical LGN/NuMA/dynein, linking G protein chemistry to division geometry.

    Evidence Pertussis toxin, siRNA, immunofluorescence and live GFP-tubulin imaging in adherent cells

    PMID:20479129

    Open questions at the time
    • Whether GEF vs chaperone activity drives spindle role unresolved
  9. 2011 High

    Defined the chaperone basis of GEF action and extended signaling to RTKs and GDI complexes: Ric-8A stabilizes the nucleotide-free Gα state via the Gα C-terminus, couples PDGFR to Gα13 for actin remodeling and migration, and dissociates RGS14·Gαi1·GPCR complexes.

    Evidence Trypsinolysis/NMR/HDX/DSC biophysics, RNAi with live imaging and in vitro pulldown, BRET and co-IP

    PMID:21771786 PMID:21853086 PMID:21880739

    Open questions at the time
    • Full structural map of nucleotide-free complex still lacking
    • RTK-to-Gα13 coupling mechanism only partially defined
  10. 2012 High

    Identified membrane-recruitment partners and a tissue-level developmental role: NCAM180 recruits Ric-8A into a Gαs complex at membrane microdomains, and Ric-8a is required in Bergmann glia for basement-membrane adhesion and cerebellar foliation, phenocopying β1 integrin loss.

    Evidence Y2H/co-IP/DRM fractionation/cAMP assays; cell-type-specific conditional knockout mice and adhesion assays

    PMID:22384181 PMID:23100420

    Open questions at the time
    • Link between Gα chaperoning and integrin-dependent adhesion mechanistically indirect
  11. 2013 Medium

    Crystallized the dual chaperone/developmental role: Ric-8A prevents polyubiquitination and proteasomal degradation of Gαi2/Gαq via direct C-terminal binding, and is required for neural crest migration and neuronal survival in vivo.

    Evidence Co-IP/MG132/ubiquitination assays with truncation mutants; Xenopus morpholino with transplant; synapsin-Cre conditional KO mice

    PMID:23588098 PMID:23665327 PMID:23977396

    Open questions at the time
    • Identity of E3 ligase acting on Gα not determined
    • Single-lab knockdown phenotypes
  12. 2014 High

    Extended the chaperone role to a definitive structural readout and a new cell-cycle function: Ric-8A regulates Vps34 at the midbody for cytokinesis abscission and adopts a closed conformation during mitosis, with cell-cycle-regulated expression.

    Evidence siRNA abscission assays, FLIM-FRET conformational biosensor, Vps34 activity assay; NCS-1/Frq2 crystallography and Drosophila genetics/electrophysiology

    PMID:24466196 PMID:25074811

    Open questions at the time
    • Trigger for the mitotic conformational switch unknown
  13. 2015 High

    Provided definitive genetic proof of chaperone function and direct structural views of the exchange mechanism: B-cell Ric-8A deletion collapses Gαi/q/13 levels, DEER reveals up to 25 Å domain separation, and Gα13 drives Src-dependent tyrosine phosphorylation and membrane translocation of Ric-8A.

    Evidence Conditional KO mice with Gα Western blots; SDSL-DEER spectroscopy; TAP-MS, phospho-mapping and Rho GTPase assays

    PMID:25605908 PMID:26232433 PMID:27096001

    Open questions at the time
    • Atomic-resolution complex structure still pending
    • Functional consequence of Tyr phosphorylation not fully defined
  14. 2016 High

    Resolved mechanistic detail and disease relevance: HDX-MS pinpointed Ric-8A-induced disruption of the Gα nucleotide-binding site, an NCS-1/Ric-8A small-molecule disruptor rescued a fragile-X model, and Ric-8A chaperoning was shown essential for oncogenic GNAQ(Q209L)-driven melanoma.

    Evidence HDX-MS with alanine scanning; NCS-1/FD44 crystallography with Drosophila behavior; inducible melanocyte KO with mouse tumor rescue

    PMID:27348266 PMID:28008853 PMID:28119500

    Open questions at the time
    • Therapeutic targeting of Ric-8A in Gαq-driven tumors not yet established
  15. 2017 Medium

    Generalized the cytoskeletal/polarity role: Ric-8A is required for actin stress fiber and focal adhesion formation, β1-integrin activation, and Gαi/LGN-mediated epithelial tight-junction assembly and cystogenesis.

    Evidence Ric8a-/- ES cells and fibroblasts with adhesion/migration readouts; siRNA MDCK 2D/3D culture with Gαi mutant rescue

    PMID:28185378 PMID:28526238

    Open questions at the time
    • Whether integrin activation is downstream of a specific Gα subunit unresolved
  16. 2018 High

    Defined a key activating post-translational switch: constitutive CK2 phosphorylation at Ser435/Thr440 is required for high-affinity Gα binding, GEF activity, and chaperone function, validated genetically in C. elegans.

    Evidence Phosphosite MS mapping, mutant GEF/chaperone assays, CRISPR genomic mutations and behavioral rescue in C. elegans

    PMID:29844055

    Open questions at the time
    • Whether CK2 phosphorylation is dynamically regulated by signals unknown
  17. 2019 High

    Delivered the apo and Gα-fragment-bound structures: Ric-8A is an armadillo/HEAT-repeat superhelix whose concave surface binds the Gα C-terminus, with a flexible C-terminal tail organizing the Gα nucleotide-binding site, and phosphorylation reorienting repeat modules.

    Evidence X-ray crystallography (apo and Gα C-terminal fragment), crosslinking MS, MD, SAXS, NMR

    PMID:31155309 PMID:31300652 PMID:31624147

    Open questions at the time
    • Full intact Ric-8A:Gα complex not yet captured
    • α5-helix rearrangement model partly computational
  18. 2020 High

    Provided the near-atomic structure of phosphorylated Ric-8A bound to nucleotide-free Gαi1, showing multi-interface engagement, ejection of the Gα C-terminus, stabilization of the empty state via the β-sheet/switch II, and a mechanism distinct from GPCRs.

    Evidence Cryo-EM plus X-ray crystallography with nanobody stabilization and phosphorylation-dependent binding analysis

    PMID:32103024

    Open questions at the time
    • Conformational trajectory of GDP release in real time not captured
    • How GTP binding triggers release structurally undefined
  19. 2021 Medium

    Identified post-translational degradation control: circPDE4B scaffolds proteasomal degradation of RIC8A, ubiquitination at K415 abrogates degradation, and the axis drives p38 MAPK signaling and cartilage breakdown in osteoarthritis.

    Evidence RNA pulldown-MS, co-IP/GST pulldown, K415 ubiquitination mapping, mouse OA model with AAV overexpression

    PMID:34039624

    Open questions at the time
    • E3 ligase for RIC8A K415 not identified
    • Single-lab disease model
  20. 2023 High

    Defined the negative regulatory switch: NCS-1 binding is mutually exclusive with Gα, traps Ric-8A in a CK2-phosphorylation-inaccessible conformation to suppress GEF activity, and is relieved by elevated Ca2+.

    Evidence Reconstitution, NCS-1/Ric-8A crystallography, GEF and CK2 phosphorylation assays, Ca2+ titration

    PMID:38018500

    Open questions at the time
    • Physiological Ca2+ contexts gating this switch in vivo not defined
  21. 2025 Medium

    Showed Ric-8A actively promotes the GTP-bound activated state even of constitutively active Gαq, reframing its role beyond folding to sustaining effector-competent active Gα.

    Evidence RIC-8A CRISPR KO cells, signaling assays, GRK2-RH domain pulldown/BRET, Ric-8A re-expression rescue

    PMID:40118458

    Open questions at the time
    • Whether this reflects chaperone-dependent folding vs direct activation promotion unresolved
    • Single cell-based study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Ric-8A's GEF, chaperone, and degradation-protective activities are coordinately partitioned across distinct cellular processes (division, migration, polarity) and the identity of the E3 ligases acting on Ric-8A and on its Gα clients remain unresolved.
  • E3 ligase for Gα subunits and for Ric-8A K415 unknown
  • Mechanism partitioning GEF vs chaperone roles in different processes undefined
  • Real-time structural trajectory of GDP release/GTP-triggered dissociation not captured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 4 GO:0005815 microtubule organizing center 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2
Partners
ADCY5AGS3GNA13GNAI1GNAQNCAM1NCS-1RGS14
Complex memberships
NCAM180:Ric-8A:Gαs complexNCS-1:Ric-8A complexRic-8A:AGS3:Gαi1 ternary complexRic-8A:Gαi1 nucleotide-free complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Mammalian 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; this complex dissociates upon GTP binding to Gα. Yeast two-hybrid screen, purification of recombinant Ric-8A, in vitro guanine nucleotide exchange assays, biochemical characterization 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; genetic epistasis places RIC-8 in the Gαo–Gαq signaling network controlling diacylglycerol production. Forward genetic screen for aldicarb-resistant mutants, cDNA analysis, immunostaining, genetic epistasis with phorbol ester rescue and dgk-1 suppression Neuron High 10985349
2000 C. elegans RIC-8 and GOA-1 (Gαo) regulate centrosome movements during early embryogenesis, including posterior centrosome rocking, P1 centrosome flattening, mitotic spindle alignment, and nuclear migration; GOA-1 localizes to cell cortices and near centrosomes. Nomarski analysis of reduction-of-function mutants, genetic interaction studies (dosage reduction), immunostaining for GOA-1 localization Genetics High 11102364
2003 Human synembryn (Ric-8A) interacts with Gαs and Gαq in yeast two-hybrid and in vitro pulldown assays, and translocates to the plasma membrane in response to carbachol (Gq-coupled) and isoproterenol (Gs-coupled) stimulation. Yeast two-hybrid screen, in vitro pulldown, in vivo confocal laser microscopy for translocation Journal of cellular physiology Medium 12652642
2004 C. elegans genetic screens demonstrate that rescue of ric-8 paralysis by Gαs pathway activation (gain-of-function mutations in Gαs, adenylyl cyclase, PKA) links RIC-8 to a third major branch (Gαs pathway) of the synaptic signaling network, acting in neurons. Forward genetic screens, high-resolution mapping, sequence analysis, pharmacological assays, transgene induction with cell-specific promoters Genetics High 15489510
2006 Ric-8A potentiates Gq-mediated ERK activation and intracellular calcium mobilization downstream of GPCRs in intact cells; siRNA knockdown reduces these responses, and membrane-targeted Ric-8A enhances them. YM-254890 (Gq inhibitor) blocks both ERK enhancement and GEF activity, confirming the Gαq-dependent mechanism. siRNA knockdown, myristoylation-tagged Ric-8A overexpression, ERK activation assays, calcium mobilization assays, pharmacological inhibition in 293T cells Genes to cells Medium 16629901
2007 Ric-8A directly interacts with the N-terminus of adenylyl cyclase type 5 (AC5) and selectively suppresses AC5 activity through a Gαi-mediated pathway; pertussis toxin or dominant-negative Gαi abolishes this suppressive effect. Pulldown assays, co-immunoprecipitation, co-localization in brain, AC5 activity assays, pertussis toxin treatment, dominant-negative Gαi expression The Biochemical journal Medium 17593019
2008 Ric-8A catalyzes rapid GDP release from the AGS3:Gαi1·GDP complex by forming a transient ternary complex (Ric-8A:AGS3:Gαi1), subsequently yielding a stable nucleotide-free Ric-8A·Gαi1 complex; this ensures unidirectional Gαi activation that cannot be reversed by AGS3. Pulldown assays, gel filtration, isothermal titration calorimetry, rapid mixing stopped-flow fluorescence spectroscopy The Journal of biological chemistry High 18541531
2009 Ric-8A interacts with Gα-gustducin and Gαi2 in taste bud cells and amplifies signal transduction of the bitter receptor hTas2R16, consistent with a role as a GEF amplifying taste GPCR signaling. Expression analysis in mouse taste cells, co-immunoprecipitation of Gα subunits with Ric-8A, functional receptor signaling assays Frontiers in cellular neuroscience Medium 19847316
2010 Ric-8A and Gαi function together to orient the mitotic spindle in mammalian adherent cells by recruiting LGN, NuMA, and dynein to the metaphase cell cortex; pertussis toxin (which blocks Ric-8A binding to Gαi) or Ric-8A knockdown similarly impairs cortical LGN/NuMA/dynein localization and spindle orientation. Pertussis toxin treatment, siRNA knockdown, immunofluorescence localization during mitosis, live-cell GFP-tubulin imaging, integrin-dependent spindle orientation assay Molecular and cellular biology High 20479129
2011 Ric-8A stabilizes nucleotide-free Gαi1 as a chaperone for the conformationally dynamic nucleotide-free state; Ric-8A-bound Gαi1[] shows increased tryptic accessibility, extensive hydrogen-deuterium exchange, and is stabilized against thermal unfolding relative to free Gαi1[]. The C-terminus of Gαi1 is a critical binding element for Ric-8A. Trypsinolysis protection assays, NMR TROSY-HSQC, hydrogen-deuterium exchange, differential scanning calorimetry, C-terminal deletion mutants PloS one High 21853086
2011 Ric-8A is critical for coupling receptor tyrosine kinases (e.g., PDGFR) to Gα13 for actin cytoskeletal reorganization (dorsal ruffle turnover and cell migration); Ric-8A knockdown slows PDGF-induced dorsal ruffle turnover and inhibits cell migration; purified Ric-8A interacts directly with Gα13 in a nucleotide-dependent manner; Ric-8A deficiency prevents Gα13 translocation to the cell cortex. RNAi knockdown, live-cell imaging of dorsal ruffles, migration assays, in vitro pulldown with purified proteins, subcellular fractionation/immunofluorescence for Gα13 localization The Journal of biological chemistry Medium 21771786
2011 Ric-8A acts on the RGS14·Gαi1·α2A-adrenergic receptor complex to facilitate dissociation of both RGS14·Gαi1 and the Gαi1-dependent RGS14·GPCR complex after receptor activation. Live-cell bioluminescence resonance energy transfer (BRET), co-immunoprecipitation The Journal of biological chemistry Medium 21880739
2012 NCAM180 interacts with Ric-8A and recruits it to the plasma membrane/detergent-resistant membrane microdomains in a dose-dependent manner; NCAM180, Ric-8A, and Gαs form a tripartite complex; Ric-8A is required for NCAM180-potentiated β-adrenergic receptor-stimulated cAMP production in neurons. Yeast two-hybrid, co-immunoprecipitation, confocal microscopy colocalization, DRM fractionation in NCAM KO vs WT brains, cAMP assays with siRNA and overexpression PloS one Medium 22384181
2012 Ric-8a is specifically required in Bergmann glia for cerebellar foliation; Ric-8a-deficient Bergmann glia fail to maintain adhesion to the basement membrane at emerging fissures, resulting in disorganized glial scaffolding, defective granule cell migration, and disrupted Purkinje cell positioning; this phenocopies β1 integrin deletion. Conditional knockout mouse (Bergmann glia-specific and granule cell-specific), histological analysis, basement membrane adhesion assays with cerebellar glia, β1 integrin conditional KO comparison The Journal of neuroscience High 23100420
2013 Ric-8A stabilizes Gαi2 and Gαq by preventing their polyubiquitination and proteasomal degradation; this requires direct Ric-8A interaction with Gα, as C-terminal truncations of Gαq/Gαi2 that abolish Ric-8A binding also abolish stabilization and suppression of ubiquitination. Co-immunoprecipitation, MG132 proteasome inhibitor treatment, ubiquitination assays in COS-7 cells, C-terminal truncation mutants of Gα Biochemical and biophysical research communications Medium 23665327
2013 Ric-8A is required for cranial neural crest (NC) cell migration and craniofacial cartilage differentiation in Xenopus; Ric-8A morphant NC cells fail to migrate directionally toward Sdf1, show reduced cell spreading, impaired focal adhesion formation, and abnormal radial migration; during migration, Ric-8A localizes to the cell membrane. Morpholino knockdown in Xenopus, in vivo transplantation assays, NC explant chemotaxis assays, immunofluorescence for focal adhesion/spreading, live confocal for Ric-8A localization Developmental biology Medium 23588098
2013 Neuronal ablation of Ric-8A in mice (synapsin I-Cre driven) causes postnatal lethality with skeletal muscle atrophy, heart muscle hypoplasia, sinoatrial node misplacement, and severe neuromuscular phenotype, demonstrating that Ric-8A activity in neurons is essential for survival. Conditional knockout mouse (synapsin I-Cre × Ric8a flox/lacZ), histological analysis, phenotypic characterization PloS one Medium 23977396
2014 Ric-8A and Gαi control cytokinesis abscission by regulating Vps34 (PI3-kinase) activity at the midbody; Ric-8A co-localizes with Vps34, Gαi, and LGN at the midbody; Ric-8A expression is post-transcriptionally regulated during the cell cycle, peaking at mitosis; FLIM-FRET shows Ric-8A adopts a closed conformation during mitosis/cytokinesis; Ric-8A knockdown delays abscission. siRNA knockdown (abscission timing, intercellular bridge length, multinucleation), FLIM-FRET biosensor, confocal colocalization, Vps34 PI3-kinase activity assay PloS one Medium 24466196
2014 Drosophila Ric8a binds to Frq2 (NCS-1 homolog) but not to the nearly identical Frq1; residues R94 and T138 in Frq2 determine binding specificity; human NCS-1 and Ric8a reproduce this interaction. Ric8a and Gαs regulate synapse number and neurotransmitter release; Frq2 negatively regulates Ric8a for synapse number control, but neurotransmitter release regulation by Ric8a is independent of Frq2 binding. Crystallographic data on Frq2, site-directed mutagenesis, co-immunoprecipitation, genetic epistasis in Drosophila, electrophysiology Journal of cell science High 25074811
2015 B lymphocyte-specific deletion of Ric-8A causes severe reduction in Gαi2/3, Gαq, and Gα13 protein levels, demonstrating Ric-8A acts as a molecular chaperone required for Gα subunit stability and membrane association; B cells show poor chemokine responses, abnormal trafficking, and loss of polarity. Conditional knockout mice (mb1-Cre and vav1-Cre × Ric8a flox/flox), Western blotting for Gα levels, chemokine response assays, B cell trafficking/positioning analysis Journal of immunology High 26232433
2015 Using SDSL-DEER spectroscopy, Ric-8A induces large-scale domain separation in the Gαi1:Ric-8A complex, with the helical and Ras-like nucleotide-binding domains pivoting apart up to 25 Å into multiple conformational states; switch I and switch II regions undergo structural rearrangements consistent with the mechanism of nucleotide exchange. Site-directed spin labeling (SDSL), double electron-electron resonance (DEER) spectroscopy, conformational ensemble analysis Proceedings of the National Academy of Sciences of the United States of America High 25605908
2015 Ric-8A potentiates Gα13-mediated RhoA, Cdc42, and p38MAPK activation; Gα13 stimulates tyrosine phosphorylation of Ric-8A (at Tyr-435, partially via Src-family kinases), and Gα13 promotes Ric-8A translocation to the plasma membrane in a Src-dependent manner; the C-terminus of Gα13 (containing the guanine-ring interaction site) is required for Gα13-Ric-8A interaction. Tandem affinity purification–mass spectrometry, serial deletion mutants of Gα13, phospho-site identification by MS, kinase inhibitor (PP2/SI) treatments, Rho GTPase activation assays Journal of molecular signaling Medium 27096001
2016 Crystal structure of NCS-1 bound to phenothiazine FD44 reveals that the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1, blocking the Ric-8A binding interface; FD44 disrupts NCS-1/Ric-8A interaction and restores normal synapse number and associative learning in a Drosophila fragile X syndrome model. Virtual screening, crystallography of NCS-1/FD44 complex, structure-activity relationship analysis, Drosophila FXS behavioral assays, synapse counting Proceedings of the National Academy of Sciences of the United States of America High 28119500
2016 Ric-8A genetic ablation in melanocytes reduces Gαq-Q209L (oncogenic) below detectable levels and completely abrogates GNAQ(Q209L)-driven melanoma tumorigenesis in mice; re-expression of Ric-8A rescues tumorigenesis, confirming Ric-8A is the chaperone required for oncogenic Gαq/11 protein folding and stability. Tamoxifen-inducible Cre-mediated Ric-8A knockout melanocyte cell line, mouse tumor graft models, Western blotting for Gαq-Q209L levels, stable Ric-8A transgene rescue Oncogenesis High 27348266
2016 HDX-MS shows that Ric-8A disrupts secondary structure of the Gαi1 Ras-like domain surrounding the nucleotide-binding site and destabilizes the Ras–helical domain interface, allowing domain separation and nucleotide release; alanine scanning of a putative Gα interaction site in Ric-8A identifies residues critical for GEF activity; Ric-8A contacts the Gα C-terminus, Switches I and II, and possibly the domain interface — distinct from GPCRs. Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS), alanine scanning mutagenesis with GEF activity assays eLife High 28008853
2017 Ric-8A regulates epithelial cell polarity for tight junction assembly and cystogenesis in 3D culture; Ric-8A knockdown delays tight junction formation and causes cyst morphogenesis defects; these effects are mediated through Gαi and LGN/AGS3; Gαi that retains LGN-binding ability but not interaction-defective mutant rescues cystogenesis. siRNA knockdown in MDCK cells (2D and 3D culture), tight junction assembly assays, cyst morphogenesis scoring, Gαi mutant rescue experiments Genes to cells Medium 28185378
2017 Ric-8A is essential for actin cytoskeleton organization and cell-ECM interactions; Ric-8a-deficient mouse embryonic stem cells and fibroblasts attach to ECM but cannot spread correctly and fail to form stress fibers or focal adhesion complexes; Ric-8A is necessary for activation of β1 integrins and integrin-mediated cell migration. Ric8a-/- mouse embryonic stem cells and fibroblasts, actin staining, focal adhesion immunofluorescence, β1 integrin activation assay, cell migration assays Experimental cell research Medium 28526238
2018 Ric-8A is constitutively phosphorylated at five serines/threonines by CK2; phosphorylation of Ser435 and Thr440 (rat; Ser436/Thr441 human) is required for high-affinity Gα binding, efficient GEF activity, and Gα folding chaperoning; C. elegans with alanine mutations at homologous sites exhibit ric-8 reduction-of-function phenotypes (reduced locomotion, defective egg laying) rescued partially by Gq stimulation; homologous Ric-8B sites are also CK2-phosphorylated. Proteomics/MS phosphosite mapping, Western blotting, phosphosite mutant analysis (GEF assay, Gα folding assay), C. elegans CRISPR genomic mutations, behavioral phenotyping, pharmacological rescue Science signaling High 29844055
2019 Crystal structure of Ric-8A reveals two principal domains: an armadillo-fold core and a flexible C-terminal tail; the Gα C-terminus binds to a highly-conserved patch on the concave surface of the armadillo domain; crosslinking mass spectrometry and MD simulations indicate the C-terminal tail helps organize the GTP-binding site of Gα; the C-terminal tail is critical for Ric-8A stability and function. X-ray crystallography (apo and Gα C-terminal fragment-bound structures), crosslinking mass spectrometry, molecular dynamics simulations, biochemical truncation analysis Nature communications High 31300652
2019 Crystal structure of Ric-8A (residues 1–452, phosphorylated at Ser435/Thr440) shows an armadillo/HEAT repeat superhelical fold; phosphorylation induces relative rotation between repeat modules as shown by SAXS normal mode modeling; NMR chemical shift perturbations confirm Gαi1 C-terminus and nucleotide-binding residues contact Ric-8A. X-ray crystallography (2.2 Å), SAXS, 2D TROSY NMR, phospho-site occupancy verification Structure High 31155309
2019 SAXS-guided steered molecular dynamics modeling of the Ric-8A/miniGαi complex indicates large-scale rearrangement of the Gα α5-helix away from its β-sheet core, with the α5-helix binding the concave surface of Ric-8A and the Gα β-sheet wrapping around the Ric-8A C-terminal armadillo domain, 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 (SMD) simulations, model scoring The Journal of biological chemistry Medium 31624147
2020 Cryo-EM and X-ray crystal structure of phosphorylated Ric-8A bound to nucleotide-free Gαi1 (nanobody-stabilized) at near-atomic resolution reveals: Ric-8A engages Gα at multiple interfaces; phosphorylation within a Ric-8A segment connecting two Gα binding sites stabilizes the complex; the Gα C-terminus is ejected from its β-sheet core dismantling the GDP binding site; Ric-8A binds the exposed Gα β-sheet and switch II to stabilize the nucleotide-free state; the mechanism differs substantially from GPCR-mediated exchange. Cryo-electron microscopy, X-ray crystallography, nanobody stabilization of complex, phosphorylation-dependent binding analysis Nature communications High 32103024
2021 circPDE4B acts as a scaffold to promote RIC8A degradation via proteasomal degradation; ubiquitination of RIC8A at K415 abrogates its degradation; the circPDE4B-RIC8A axis regulates downstream p38 MAPK signaling; RIC8A overexpression promotes cartilage matrix breakdown in a mouse OA model. RNA pulldown–mass spectrometry, co-immunoprecipitation, GST pulldown, RNA immunoprecipitation, ubiquitination mapping (K415 mutant), mouse OA model with AAV overexpression Annals of the rheumatic diseases Medium 34039624
2023 NCS-1 binding to Ric-8A is mutually exclusive with Gα binding; NCS-1 induces a structural rearrangement in Ric-8A that traps it in a conformation inaccessible to CK2-mediated phosphorylation, thereby negatively regulating Ric-8A GEF activity; increasing Ca2+ concentration restores Ric-8A GEF activity toward Gα even in the presence of NCS-1. Reconstitution of NCS-1/Ric-8A complexes, crystallography of NCS-1/Ric-8A interface, GEF activity assays, CK2 phosphorylation assays, Ca2+ titration experiments eLife High 38018500
2025 In RIC-8A KO cells, myristoylated constitutively active αqQL/P mutants that are normally YM-254890-resistant become YM-sensitive, and reintroduction of Ric-8A reverses this sensitivity; Ric-8A enhances activation state of αqQL, its effector binding (via GRK2-RH domain BRET), and signaling, demonstrating Ric-8A promotes GTP-bound activated state of constitutively active Gαq. RIC-8A KO cells (CRISPR), signaling assays, pulldown with GRK2 RH domain, BRET assays, Ric-8A re-expression rescue 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 260 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 107 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 89 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 36 28119500
2014 The guanine-exchange factor Ric8a binds to the Ca²⁺ sensor NCS-1 to regulate synapse number and neurotransmitter release. Journal of cell science 29 25074811
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
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
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 26 23100420
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
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 12 23977396
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 9 29966094
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
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
2023 The neuronal calcium sensor NCS-1 regulates the phosphorylation state and activity of the Gα chaperone and GEF Ric-8A. eLife 4 38018500
2017 RIC8A is essential for the organisation of actin cytoskeleton and cell-matrix interaction. Experimental cell research 4 28526238
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

Missed literature

Know a paper Affinage missed for RIC8A? Flag it for the maintainers and the community.

No submissions yet.