{"doi":"10.64898/2025.12.24.696424","title":"Intrinsic conformational equilibria position arrestin-2 for activation","abstract":"Arrestins regulate G protein-coupled receptor (GPCR) signaling by undergoing large-scale conformational rearrangements, yet the solution-state equilibria that underlie arrestin pre-activation remain poorly defined. Here, we use methyl-specific nuclear magnetic resonance spectroscopy, temperature-dependent chemical shift analysis, and relaxation measurements to characterize the intrinsic conformational landscape of full-length human arrestin-2 in solution. We identify two distinct equilibria with separable thermodynamic and kinetic signatures. A slow, enthalpically-favored process sensed by interdomain isoleucines I241 and I317 populates an active-like, interdomain-twisted conformation at physiological temperatures. In parallel, a faster, globally distributed equilibrium consistent with C-terminal tail release exhibits opposing thermodynamic behavior. Dynamic analyses reveal localized rigidification in the active-like minor states despite arrestin's overall flexibility, while backbone relaxation data indicate widespread μs-ms conformational exchange. Together, these results demonstrate that arrestin-2 intrinsically samples activation-relevant conformations in the absence of binding partners, providing a solution-state framework for arrestin pre-activation and signaling competence.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":587173,"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":0.9487,"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":1310251,"name":"Kerem Kahraman","orcid":"0000-0002-7992-5908","position":1,"is_corresponding":false},{"id":1374199,"name":"Mingzhe Pan","orcid":null,"position":2,"is_corresponding":false},{"id":824146,"name":"Çağdaş Dağ","orcid":"0000-0003-1595-431X","position":3,"is_corresponding":false},{"id":346055,"name":"Marco Tonelli","orcid":"0000-0002-7700-5745","position":4,"is_corresponding":false},{"id":722013,"name":"Scott A. Robson","orcid":"0000-0002-0529-0399","position":5,"is_corresponding":false},{"id":1502793,"name":"Joshua J Ziarek","orcid":null,"position":6,"is_corresponding":false},{"id":1220190,"name":"Tucker J. Shriver","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:59:36.020030Z","pmid":"41509251","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":[]}