A universal allosteric mechanism for G protein activation.

Autor:	Knight KM; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Ghosh S; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA., Campbell SL; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Lefevre TJ; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA., Olsen RHJ; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Smrcka AV; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA., Valentin NH; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Yin G; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Vaidehi N; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. Electronic address: nvaidehi@coh.org., Dohlman HG; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: hdohlman@med.unc.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Apr 01; Vol. 81 (7), pp. 1384-1396.e6. Date of Electronic Publication: 2021 Feb 25.
DOI:	10.1016/j.molcel.2021.02.002
Abstrakt:	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. Competing Interests: Declaration of interests R.H.J.O. is a co-inventor of the TRUPATH technology and could receive royalties. This relationship has been disclosed to and is under management by UNC-Chapel Hill. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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