{"doi":"10.1002/pro.70383","title":"Membrane‐forming phospholipids allosterically modulate native‐state prolyl isomerization in a <scp>CNG</scp> channel","abstract":"Ion channel activity is intricately linked to the surrounding lipid environment, yet the molecular effects of lipid-mediated regulation remain largely understudied. Here, we show that membrane-forming phospholipids, which are known to modulate the activity of the cyclic nucleotide-gated channel SthK from Spirochaeta thermophila, exhibit effects that extend well beyond the membrane boundary. Using stopped-flow flux assays, we demonstrate that anionic lipids, which are known to promote channel opening, also affect the fast-to-slow activation ratio and the cAMP potency in SthK. Enzymatic catalysis studies confirm that this occurs by altering the cis/trans equilibrium at Pro300 in the apo state. Additionally, cryogenic electron microscopy structures of SthK reveal lipid-dependent conformational changes that propagate from the bundle crossing into the cytosolic domains. All observed effects correlate with the electronegativity of the lipid headgroup, indicating a common underlying mechanism. Our results highlight membrane-forming phospholipids as allosteric regulators of SthK, controlling multiple functional characteristics of the channel.","journal":"Protein Science","year":2025,"id":548717,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"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":1442422,"name":"Robert D. Latvala","orcid":"0009-0008-2123-2982","position":1,"is_corresponding":false},{"id":1442892,"name":"Aisha S. Kuforiji","orcid":null,"position":2,"is_corresponding":false},{"id":368429,"name":"Philipp A. M. Schmidpeter","orcid":"0000-0003-2871-9706","position":3,"is_corresponding":false},{"id":1111863,"name":"Ashley J. Newton","orcid":"0009-0002-3771-2709","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:54:03.053965Z","pmid":"41263484","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":[]}