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Nature. 2015 Aug 13;524(7564):173-179. doi: 10.1038/nature14663. Epub 2015 Jul 6.

Universal allosteric mechanism for Gα activation by GPCRs.

Author information

1
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
2
Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland.
3
Department of Biology, ETH Zurich, Zurich, Switzerland.
#
Contributed equally

Abstract

G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are ∼800 human GPCRs and 16 different Gα genes, this raises the question of whether a universal allosteric mechanism governs Gα activation. Here we show that different GPCRs interact with and activate Gα proteins through a highly conserved mechanism. Comparison of Gα with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-Gα system diversified rapidly, while conserving the allosteric activation mechanism.

PMID:
26147082
PMCID:
PMC4866443
DOI:
10.1038/nature14663
[Indexed for MEDLINE]
Free PMC Article

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