Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif

Alain Ibáñez de Opakua, Kshitij Parag-Sharma, Vincent DiGiacomo, Nekane Merino, Anthony Leyme, Arthur Marivin, Maider Villate, Lien T. Nguyen, Miguel Angel de la Cruz-Morcillo, Juan B. Blanco-Canosa, Sekar Ramachandran, George S. Baillie, Richard A. Cerione, Francisco J. Blanco () and Mikel Garcia-Marcos ()
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Alain Ibáñez de Opakua: CIC bioGUNE
Kshitij Parag-Sharma: Boston University School of Medicine
Vincent DiGiacomo: Boston University School of Medicine
Nekane Merino: CIC bioGUNE
Anthony Leyme: Boston University School of Medicine
Arthur Marivin: Boston University School of Medicine
Maider Villate: CIC bioGUNE
Lien T. Nguyen: Boston University School of Medicine
Miguel Angel de la Cruz-Morcillo: Boston University School of Medicine
Juan B. Blanco-Canosa: IRB Barcelona
Sekar Ramachandran: Cornell University
George S. Baillie: Institute of Cardiovascular and Medical Sciences, University of Glasgow
Richard A. Cerione: Cornell University
Francisco J. Blanco: CIC bioGUNE
Mikel Garcia-Marcos: Boston University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Heterotrimeric G proteins are quintessential signalling switches activated by nucleotide exchange on Gα. Although activation is predominantly carried out by G-protein-coupled receptors (GPCRs), non-receptor guanine-nucleotide exchange factors (GEFs) have emerged as critical signalling molecules and therapeutic targets. Here we characterize the molecular mechanism of G-protein activation by a family of non-receptor GEFs containing a Gα-binding and -activating (GBA) motif. We combine NMR spectroscopy, computational modelling and biochemistry to map changes in Gα caused by binding of GBA proteins with residue-level resolution. We find that the GBA motif binds to the SwitchII/α3 cleft of Gα and induces changes in the G-1/P-loop and G-2 boxes (involved in phosphate binding), but not in the G-4/G-5 boxes (guanine binding). Our findings reveal that G-protein-binding and activation mechanisms are fundamentally different between GBA proteins and GPCRs, and that GEF-mediated perturbation of nucleotide phosphate binding is sufficient for Gα activation.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15163

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DOI: 10.1038/ncomms15163

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