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J Biol Chem. 2016 Feb 26;291(9):4742-53. doi: 10.1074/jbc.M115.702605. Epub 2015 Dec 24.

Dynamic Coupling and Allosteric Networks in the α Subunit of Heterotrimeric G Proteins.

Author information

1
From the Department of Computational Medicine and Bioinformatics.
2
Cell and Developmental Biology, and the Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455.
3
Pharmacology, University of Michigan, Ann Arbor, Michigan 48109.
4
the Department of Biomedicine, University of Bergen, 5020 Bergen, Norway, and.
5
the Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455.
6
From the Department of Computational Medicine and Bioinformatics, bjgrant@umich.edu.

Abstract

G protein α subunits cycle between active and inactive conformations to regulate a multitude of intracellular signaling cascades. Important structural transitions occurring during this cycle have been characterized from extensive crystallographic studies. However, the link between observed conformations and the allosteric regulation of binding events at distal sites critical for signaling through G proteins remain unclear. Here we describe molecular dynamics simulations, bioinformatics analysis, and experimental mutagenesis that identifies residues involved in mediating the allosteric coupling of receptor, nucleotide, and helical domain interfaces of Gαi. Most notably, we predict and characterize novel allosteric decoupling mutants, which display enhanced helical domain opening, increased rates of nucleotide exchange, and constitutive activity in the absence of receptor activation. Collectively, our results provide a framework for explaining how binding events and mutations can alter internal dynamic couplings critical for G protein function.

KEYWORDS:

G protein; allosteric regulation; bioinformatics; molecular dynamics; mutagenesis

PMID:
26703464
PMCID:
PMC4813496
[Available on 2017-02-26]
DOI:
10.1074/jbc.M115.702605
[Indexed for MEDLINE]
Free PMC Article

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