{"doi":"10.1101/2025.06.06.658200","title":"Membrane phosphoinositides allosterically tune β-arrestin dynamics to facilitate GPCR core engagement","abstract":"SUMMARY Arrestin proteins bind active G protein-coupled receptors (GPCRs) through coordinated protein-protein, protein-phosphate, and protein-lipid interactions to attenuate G protein signaling and promote GPCR internalization and trafficking. While there are hundreds of diverse GPCRs, only two β-arrestin isoforms (βarrs) must recognize and engage this wide range of receptors with varied phosphorylation patterns. Traditional models suggest that βarr activation requires displacement of its autoinhibitory C-tail by a phosphorylated GPCR C-terminus; however, this paradigm fails to explain how minimally phosphorylated GPCRs still complex with βarrs. Using single-molecule Förster resonance energy transfer imaging and hydrogen-deuterium exchange mass spectrometry, we observe basal dynamics in which the βarr1 C-tail spontaneously releases from the N-domain, transiently adopting an active conformation that can facilitate binding of the phosphorylated GPCR C-terminus. We further demonstrate the importance of an intermediate state of βarr1 arising from spontaneous C-tail release stabilized by the membrane phosphoinositide PI(4,5)P 2 . Both PI(4,5)P 2 and mutations in the proximal or middle regions of the C-tail shift βarr1 towards a partially released state, revealing an allosteric connection that informs a refined model for βarr activation. In this model, membrane engagement conformationally primes βarrs prior to receptor binding, thereby explaining how βarrs are recruited by diverse GPCRs, even those with limited C-terminal phosphorylation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558206,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":476214,"name":"Jonathan Deutsch","orcid":null,"position":1,"is_corresponding":false},{"id":457007,"name":"Yuqi Shi","orcid":"0009-0000-0825-7933","position":2,"is_corresponding":false},{"id":264644,"name":"Dirk H. Siepe","orcid":"0000-0002-0009-8023","position":3,"is_corresponding":false},{"id":251459,"name":"Matthieu Masureel","orcid":"0000-0002-4059-6166","position":4,"is_corresponding":false},{"id":1043047,"name":"Weijing Liu","orcid":"0000-0003-2322-0500","position":5,"is_corresponding":false},{"id":89978,"name":"Rosa Viner","orcid":"0000-0003-0550-5545","position":6,"is_corresponding":false},{"id":255551,"name":"Asuka Inoue","orcid":"0000-0003-0805-4049","position":7,"is_corresponding":false},{"id":236408,"name":"Steven Chu","orcid":"0000-0002-4572-0154","position":8,"is_corresponding":false},{"id":251465,"name":"Brian K. Kobilka","orcid":"0000-0001-5958-3990","position":9,"is_corresponding":false},{"id":802248,"name":"Rabindra V. Shivnaraine","orcid":null,"position":10,"is_corresponding":false},{"id":690841,"name":"John Janetzko","orcid":"0000-0003-1604-2515","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40501946","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":[]}