{"doi":"10.1016/j.cell.2022.03.042","title":"GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision","abstract":"β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in its basal state. Its engagement with a phosphopeptide mimicking phosphorylated receptor tail efficiently releases the β-arrestin tail from its N domain to assume distinct conformations. Unexpectedly, we find that β-arrestin binding to phosphorylated receptor, with a phosphorylation barcode identical to the isolated phosphopeptide, is highly inefficient and that agonist-promoted receptor activation is required for β-arrestin activation, consistent with the release of a sequestered receptor C tail. These findings, together with focused cellular investigations, reveal that agonism and receptor C-tail release are specific determinants of the rate and efficiency of β-arrestin activation by phosphorylated receptor. We infer that receptor phosphorylation patterns, in combination with receptor agonism, synergistically establish the strength and specificity with which diverse, downstream β-arrestin-mediated events are directed.","journal":"Cell","year":2022,"id":233985,"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":110,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241927,"name":"Daniel S. Terry","orcid":"0000-0001-9021-0084","position":1,"is_corresponding":false},{"id":848571,"name":"G. Glenn Gregorio","orcid":"0000-0001-8677-133X","position":2,"is_corresponding":false},{"id":592095,"name":"Alem W. Kahsai","orcid":"0000-0001-9272-4484","position":3,"is_corresponding":false},{"id":274339,"name":"Alessandro Borgia","orcid":"0000-0002-4701-8967","position":4,"is_corresponding":false},{"id":671002,"name":"Bing Xie","orcid":"0000-0002-1692-7199","position":5,"is_corresponding":false},{"id":848572,"name":"Arnab Modak","orcid":"0000-0001-7262-0143","position":6,"is_corresponding":false},{"id":641851,"name":"Ying Zhu","orcid":"0000-0002-3184-4447","position":7,"is_corresponding":false},{"id":268406,"name":"Wonjo Jang","orcid":"0000-0002-1928-8978","position":8,"is_corresponding":false},{"id":848573,"name":"Alekhya Govindaraju","orcid":"0000-0003-4967-3612","position":9,"is_corresponding":false},{"id":703157,"name":"Li-Yin Huang","orcid":"0000-0001-6357-0113","position":10,"is_corresponding":false},{"id":255551,"name":"Asuka Inoue","orcid":"0000-0003-0805-4049","position":11,"is_corresponding":false},{"id":268407,"name":"Nevin A. Lambert","orcid":"0000-0001-7550-0921","position":12,"is_corresponding":false},{"id":271822,"name":"Vsevolod V. Gurevich","orcid":"0000-0002-3950-5351","position":13,"is_corresponding":false},{"id":352958,"name":"Lei Shi","orcid":"0000-0002-4137-096X","position":14,"is_corresponding":false},{"id":239850,"name":"Robert J. Lefkowitz","orcid":"0000-0003-1472-7545","position":15,"is_corresponding":false},{"id":241930,"name":"Scott C. Blanchard","orcid":"0000-0003-2717-9365","position":16,"is_corresponding":false},{"id":307532,"name":"Jonathan A. Javitch","orcid":"0000-0001-7395-2967","position":17,"is_corresponding":false},{"id":310843,"name":"Wesley B. Asher","orcid":"0000-0001-7437-218X","position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-19T00:21:31.237180Z","pmid":"35483373","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":[]}