{"doi":"10.17615/h4wd-7g75","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 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. We show further that proton binding induces changes in conformation that promote Gα phosphorylation and suppress receptor-initiated signaling. Together, our computational, biophysical and cellular analyses reveal a new and unexpected function for G proteins as mediators of stress-response signaling.","journal":"UNC Libraries","year":2020,"id":136068,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":304965,"name":"Daniel G. Isom","orcid":"0000-0001-5637-2370","position":1,"is_corresponding":false},{"id":594433,"name":"Sarah T. Clement","orcid":null,"position":2,"is_corresponding":false},{"id":543829,"name":"Rachael Baker","orcid":null,"position":3,"is_corresponding":false},{"id":406789,"name":"Henrik Dohlman","orcid":"0000-0003-2443-0729","position":4,"is_corresponding":false},{"id":593672,"name":"Vishwajith Sridharan","orcid":"0000-0001-6766-2285","position":5,"is_corresponding":false},{"id":324397,"name":"David M. Smalley","orcid":"0000-0003-3239-9055","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:35.237665Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}