title: Protons as second messenger regulators of G protein signaling.
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.
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. disom@unc.edu
authors: Daniel G
authors: DG
authors: Isom
authors: Vishwajith
authors: V
authors: Sridharan
authors: Rachael
authors: R
authors: Baker
authors: Sarah T
authors: ST
authors: Clement
authors: David M
authors: DM
authors: Smalley
authors: Henrik G
authors: HG
authors: Dohlman
mesh_terms: D000465:Algorithms; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011522:Protons; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D013312:Stress, Physiological; D013696:Temperature
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D011522:Protons; D043562:Receptors, G-Protein-Coupled; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
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