A Universal Allosteric Mechanism for G Protein Activation

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Feb 26

PMID 33636126

Citations 31

Authors

Kevin M Knight

Soumadwip Ghosh

Sharon L Campbell

Tyler J Lefevre

Reid H J Olsen

Alan V Smrcka

Natalie H Valentin

Guowei Yin

Nagarajan Vaidehi

Henrik G Dohlman

Affiliations

Soon will be listed here.

Abstract

G proteins play a central role in signal transduction and pharmacology. Signaling is initiated by cell-surface receptors, which promote guanosine triphosphate (GTP) binding and dissociation of Gα from the Gβγ subunits. Structural studies have revealed the molecular basis of subunit association with receptors, RGS proteins, and downstream effectors. In contrast, the mechanism of subunit dissociation is poorly understood. We use cell signaling assays, molecular dynamics (MD) simulations, and biochemistry and structural analyses to identify a conserved network of amino acids that dictates subunit release. In the presence of the terminal phosphate of GTP, a glycine forms a polar network with an arginine and glutamate, putting torsional strain on the subunit binding interface. This "G-R-E motif" secures GTP and, through an allosteric link, discharges the Gβγ dimer. Replacement of network residues prevents subunit dissociation regardless of agonist or GTP binding. These findings reveal the molecular basis of the final committed step of G protein activation.

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