Structural basis for GPCR-independent activation of heterotrimeric Gi proteins

Proceedings of the National Academy of Sciences of the United States of America
Nicholas KalogriopoulosIrina Kufareva

Abstract

Heterotrimeric G proteins are key molecular switches that control cell behavior. The canonical activation of G proteins by agonist-occupied G protein-coupled receptors (GPCRs) has recently been elucidated from the structural perspective. In contrast, the structural basis for GPCR-independent G protein activation by a novel family of guanine-nucleotide exchange modulators (GEMs) remains unknown. Here, we present a 2.0-Å crystal structure of Gαi in complex with the GEM motif of GIV/Girdin. Nucleotide exchange assays, molecular dynamics simulations, and hydrogen-deuterium exchange experiments demonstrate that GEM binding to the conformational switch II causes structural changes that allosterically propagate to the hydrophobic core of the Gαi GTPase domain. Rearrangement of the hydrophobic core appears to be a common mechanism by which GPCRs and GEMs activate G proteins, although with different efficiency. Atomic-level insights presented here will aid structure-based efforts to selectively target the noncanonical G protein activation.

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Citations

Jan 23, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Dhiraj Srivastava, Nikolai O Artemyev
Jan 18, 2020·The Journal of Biological Chemistry·Arthur MarivinMikel Garcia-Marcos
Apr 24, 2020·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Michael GetzPradipta Ghosh
Jan 9, 2021·Journal of Structural Biology·Donghee HamKa Young Chung
Nov 4, 2020·Proceedings of the National Academy of Sciences of the United States of America·Nicholas A KalogriopoulosPradipta Ghosh
Mar 7, 2021·The Journal of Biological Chemistry·Jason EarPradipta Ghosh
May 15, 2021·Trends in Pharmacological Sciences·Pradipta Ghosh, Madhubanti Mullick

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