ArticleThe Journal of biological chemistry2011
G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 48 citations in OpenAlex.
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk.Cell reports · 2024Article
- Does one plus one always equal two? Structural differences between nesfatin-1, -2, and nesfatin-1/2.Cell communication and signaling : CCS · 2022Article
- CaFaculty reviews · 2022Review
- The Multifaceted Nature of Nucleobindin-2 in Carcinogenesis.International journal of molecular sciences · 2021Review
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- Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein.eLife · 2020Article
- Regulating cellular cyclic adenosine monophosphate: "Sources," "sinks," and now, "tunable valves".Wiley interdisciplinary reviews. Systems biology and medicine · 2020Review
- The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer.Life science alliance · 2020Article
- 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 · 2020Article
- DAPLE protein inhibits nucleotide exchange on GαThe Journal of biological chemistry · 2020Article
- Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors.Scientific reports · 2019Article
- Structural basis for GPCR-independent activation of heterotrimeric Gi proteins.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- GPCR-independent activation of G proteins promotes apical cell constriction in vivo.The Journal of cell biology · 2019Article
- A biochemical and genetic discovery pipeline identifies PLCδ4b as a nonreceptor activator of heterotrimeric G-proteins.The Journal of biological chemistry · 2018Article
- Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity.Cell reports · 2018Article
- Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple.Science signaling · 2018Article
- Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif.Nature communications · 2017Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Heterotrimeric G proteins are molecular switches modulated by families of structurally and functionally related regulators. GIV (Gα-interacting vesicle-associated protein) is the first non-receptor guanine nucleotide exchange factor (GEF) that activates Gα(i) subunits via a defined, evolutionarily conserved motif. Here we found that Calnuc and NUCB2, two highly homologous calcium-binding proteins, share a common motif with GIV for Gα(i) binding and activation. Bioinformatics searches and structural analysis revealed that Calnuc and NUCB2 possess an evolutionarily conserved motif with sequence and structural similarity to the GEF sequence of GIV. Using in vitro pulldown and competition assays, we demonstrate that this motif binds preferentially to the inactive conformation of Gα(i1) and Gα(i3) over other Gα subunits and, like GIV, docks onto the α3/switch II cleft. Calnuc binding was impaired when Lys-248 in the α3 helix of Gα(i3) was replaced with M, the corresponding residue in Gα(o), which does not bind to Calnuc. Moreover, mutation of hydrophobic residues in the conserved motif predicted to dock on the α3/switch II cleft of Gα(i3) impaired the ability of Calnuc and NUCB2 to bind and activate Gα(i3) in vitro. We also provide evidence that calcium binding to Calnuc and NUCB2 abolishes their interaction with Gα(i3) in vitro and in cells, probably by inducing a conformational change that renders the Gα(i)-binding residues inaccessible. Taken together, our results identify a new type of Gα(i)-regulatory motif named the GBA motif (for Gα-binding and -activating motif), which is conserved across different proteins throughout evolution. These findings provide the structural basis for the properties of Calnuc and NUCB2 binding to Gα subunits and its regulation by calcium ions.
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