Universal allosteric mechanism for Gα activation by GPCRs

Tilman Flock (), Charles N. J. Ravarani, Dawei Sun, A. J. Venkatakrishnan, Melis Kayikci, Christopher G. Tate, Dmitry B. Veprintsev and M. Madan Babu ()
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Tilman Flock: MRC Laboratory of Molecular Biology
Charles N. J. Ravarani: MRC Laboratory of Molecular Biology
Dawei Sun: Laboratory of Biomolecular Research, Paul Scherrer Institut
A. J. Venkatakrishnan: MRC Laboratory of Molecular Biology
Melis Kayikci: MRC Laboratory of Molecular Biology
Christopher G. Tate: MRC Laboratory of Molecular Biology
Dmitry B. Veprintsev: Laboratory of Biomolecular Research, Paul Scherrer Institut
M. Madan Babu: MRC Laboratory of Molecular Biology

Nature, 2015, vol. 524, issue 7564, 173-179

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14663

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