Ibáñez de Opakua, A. et al. (2017) Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif. Nature Communications, 8, 15163. (doi: 10.1038/ncomms15163) (PMID:28516903) (PMCID:PMC5454376)
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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.
Item Type: | Articles |
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Additional Information: | This work was supported by NIH grants R01GM108733, R01GM112631, American Cancer Society grants RSG-13-362-01-TBE and IRG-72-001-36, and the Karin Grunebaum Foundation (to MG-M) and CTQ2014-56966-R (to FJB). VDG is a recipient of a postdoctoral fellowship from the Hartwell Foundation. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Baillie, Professor George |
Authors: | Ibáñez de Opakua, A., Parag-Sharma, K., DiGiacomo, V., Merino, N., Leyme, A., Marivin, A., Villate, M., Nguyen, L. T., de la Cruz-Morcillo, M. A., Blanco-Canosa, J. B., Ramachandran, S., Baillie, G. S., Cerione, R. A., Blanco, F. J., and Garcia-Marcos, M. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Nature Communications |
Publisher: | Nature Research |
ISSN: | 2041-1723 |
ISSN (Online): | 2041-1723 |
Copyright Holders: | Copyright © 2017 The Authors |
First Published: | First published in Nature Communications 8:15163 |
Publisher Policy: | Reproduced under a Creative Commons License |
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