{"doi":"10.1074/jbc.m114.608661","title":"Pivotal Role of Extended Linker 2 in the Activation of Gα by G Protein-coupled Receptor","abstract":null,"journal":"Journal of Biological Chemistry","year":2015,"id":597924,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345960,"name":"Yutong Sun","orcid":"0000-0002-9368-2957","position":1,"is_corresponding":false},{"id":477920,"name":"J. Jillian Zhang","orcid":null,"position":2,"is_corresponding":false},{"id":293615,"name":"Xin-Yun Huang","orcid":null,"position":3,"is_corresponding":false},{"id":292041,"name":"Jianyun Huang","orcid":"0000-0002-2147-8826","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Pivotal Role of Extended Linker 2 in the Activation of Gα by G Protein-coupled Receptor","abstract":"G protein-coupled receptors (GPCRs) relay extracellular signals mainly to heterotrimeric G-proteins (Gαβγ) and they are the most successful drug targets. The mechanisms of G-protein activation by GPCRs are not well understood. Previous studies have revealed a signal relay route from a GPCR via the C-terminal α5-helix of Gα to the guanine nucleotide-binding pocket. Recent structural and biophysical studies uncover a role for the opening or rotating of the α-helical domain of Gα during the activation of Gα by a GPCR. Here we show that β-adrenergic receptors activate eight Gα s mutant proteins (from a screen of 66 Gα s mutants) that are unable to bind Gβγ subunits in cells. Five of these eight mutants are in the αF/Linker 2/β2 hinge region (extended Linker 2) that connects the Ras-like GTPase domain and the α-helical domain of Gα s . This extended Linker 2 is the target site of a natural product inhibitor of G q . Our data show that the extended Linker 2 is critical for Gα activation by GPCRs. We propose that a GPCR via its intracellular loop 2 directly interacts with the β 2 /β 3 loop of Gα to communicate to Linker 2, resulting in the opening and closing of the α-helical domain and the release of GDP during G-protein activation.G protein-coupled receptors mainly signal through heterotrimeric G-proteins. Results We have demonstrated that mutations in the extended Linker 2 impaired the activation of Gα s by β-adrenergic receptors. Conclusion We have proposed a potential novel conduit from β-adrenergic receptors to the helical domain of Gα s subunit via the extended Linker 2. Significance Our systematic mutagenesis studies provide insights into the activation mechanism of G-proteins by receptors.","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25414258","pmcid":"PMC4281731","openalex_id":"https://openalex.org/W1984991271","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"HL 91525","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL091525","title":null}],"total_grants":2,"fwci":0.5198,"citation_percentile":0.62992422,"influential_citations":0,"citation_trend":[{"year":2015,"count":2},{"year":2016,"count":2},{"year":2020,"count":1},{"year":2022,"count":2},{"year":2024,"count":2},{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"http://www.jbc.org/article/S0021925820579283/pdf","host_type":"journal"},{"url":"http://www.jbc.org/article/S0021925820579283/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820579283?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820579283?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1074/jbc.M114.608661","host_type":"publisher"},{"url":"https://doi.org/10.1074/jbc.m114.608661","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25414258","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4281731","host_type":"repository"}],"fields_of_study":["Receptor Mechanisms and Signaling","Protein Kinase Regulation and GTPase Signaling","Neuropeptides and Animal Physiology"],"mesh_terms":["Amino Acid Sequence","Binding Sites","Escherichia coli","Gene Expression Regulation","Humans","Models, Molecular","Molecular Sequence Data","Mutation","Protein Binding","Receptors, Adrenergic, beta","Recombinant Proteins","Signal Transduction","Gene Expression","Protein Structure, Secondary","Protein Structure, Tertiary","GTP-Binding Protein alpha Subunits, Gs","GTP-Binding Protein beta Subunits","GTP-Binding Protein gamma Subunits","HEK293 Cells","Hydrophobic and Hydrophilic Interactions"],"keywords":["Heterotrimeric G protein","G protein-coupled receptor","Linker","G protein","GTPase-activating protein","Receptor","Cell biology","G beta-gamma complex","Chemistry","GTPase","Mutant","Biochemistry","Biophysics","Biology","Gene","Signal transduction","Signaling","Cell signaling","second messenger"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T14:36:30.773598Z","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":[]}