{"doi":"10.1101/2020.04.26.062299","title":"Dynamics-driven allostery underlies pre-activation of the regulatory Ca <sup>2+</sup> -ATPase/phospholamban complex","abstract":"ABSTRACT Sarcoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA) and phospholamban (PLB) are essential for intracellular Ca 2+ transport in myocytes. Ca 2+ -dependent activation of SERCA–PLB provides a rheostat function that regulates cytosolic and SR Ca 2+ levels. While experimental and computational studies alone have led to a greater insight into the mechanisms for SERCA–PLB regulation, the structural changes induced by Ca 2+ binding and how those are communicated to couple enzymatic activity with active transport remain poorly understood. Therefore, we have performed atomistic simulations totaling 32.7 μs and cell-based intramolecular fluorescence resonance energy transfer (FRET) experiments to determine structural changes of PLB-bound SERCA in response to Ca 2+ binding. Complementary simulations and experiments showed structural disorder underlies PLB inhibition of SERCA, and Ca 2+ binding is sufficient to shift the protein population toward a structurally ordered state of the complex. This structural transition results in a redistribution of structural states toward a partially closed conformation of SERCA’s cytosolic headpiece. Closure is accompanied by functional interactions between the N-domain β5-β6 loop and the A-domain. Regulation of these key structural elements indicate that Ca 2+ is a critical mediator of allosteric signaling that dictates structural changes and motions that pre-activate SERCA–PLB. These findings provide direct support that dynamically driven protein allostery underlies PLB regulation of SERCA. These functional insights at unprecedented spatiotemporal resolution suggest a general modular architecture mechanism for dynamic regulation of the SERCA–PLB complex. Understanding these mechanisms is of paramount importance to guide therapeutic modulation of SERCA and other evolutionarily related ion-motive ATPases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129412,"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":0.9542,"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":451871,"name":"Rodrigo Aguayo‐Ortiz","orcid":"0000-0001-9455-5397","position":1,"is_corresponding":false},{"id":406903,"name":"Seth L. Robia","orcid":"0000-0002-1193-9510","position":2,"is_corresponding":false},{"id":451872,"name":"L. Michel Espinoza‐Fonseca","orcid":"0000-0002-7356-5681","position":3,"is_corresponding":false},{"id":580982,"name":"Olga N. Raguimova","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:15:45.920615Z","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":[]}