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Mol Cell. 2013 Aug 22;51(4):531-8. doi: 10.1016/j.molcel.2013.07.012. Epub 2013 Aug 15.

Protons as second messenger regulators of G protein signaling.

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  • 1Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. disom@unc.edu

Abstract

In response to environmental stress, cells often generate pH signals that serve to protect vital cellular components and reprogram gene expression for survival. A major barrier to our understanding of this process has been the identification of signaling proteins that detect changes in intracellular pH. To identify candidate pH sensors, we developed a computer algorithm that searches proteins for networks of proton-binding sidechains. This analysis indicates that Gα subunits, the principal transducers of G protein-coupled receptor (GPCR) signals, are pH sensors. Our structure-based calculations and biophysical investigations reveal that Gα subunits contain networks of pH-sensing sidechains buried between their Ras and helical domains. Further, we show that proton binding induces changes in conformation that promote Gα phosphorylation and suppress receptor-initiated signaling. Together, our computational, biophysical, and cellular analyses reveal an unexpected function for G proteins as mediators of stress-response signaling.

Copyright © 2013 Elsevier Inc. All rights reserved.

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