{"doi":"10.1016/j.jlr.2025.100929","title":"The congenital APOA1 K107del mutation disrupts the lipid-free conformation of monomeric APOA1 and impairs oligomerization","abstract":"Apolipoprotein A-I (APOA1) oligomerization is thought to be essential for high-density lipoprotein (HDL) formation and metabolism. Naturally occurring mutations can disrupt normal APOA1 folding and self-association, leading to dysfunctional HDL formation and cardiovascular disease. The congenital APOA1 variant p.K131del (APOA1 K107del ) has been associated with cardiovascular pathologies such as low HDL-cholesterol levels and aortic amyloidosis, and multiple studies indicate structural changes in APOA1 conformation underlie associated dysfunction. In the current study, we confirmed that APOA1 K107del exhibits no notable defect in lipid-binding. However, using polyacrylamide gel electrophoresis (PAGE) and size-exclusion chromatography (SEC), we found that loss of lysine 107 resulted in a remarkable shift in the distribution of APOA1 oligomers with a much higher proportion of monomers present in APOA1 K107del compared to wild-type APOA1. Further investigation using quantitative cross-linking revealed a major disruption of interactions in helical regions reported to participate in domain swaps necessary for proper self-association. This structural disruption appears to impair N- and C-termini interactions and dynamics that lead to non-specific aggregation. These findings support the hypothesis that lysine 107 is critical for proper folding and self-association of lipid-free APOA1 which could impact HDL biogenesis.","journal":"Journal of Lipid Research","year":2025,"id":579364,"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":0.953,"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":1489560,"name":"Marina González","orcid":"0000-0002-3363-9308","position":1,"is_corresponding":false},{"id":1489973,"name":"Horacio A. Garda","orcid":null,"position":2,"is_corresponding":false},{"id":1489561,"name":"Romina F. Vázquez","orcid":"0000-0002-8779-3503","position":3,"is_corresponding":false},{"id":1489974,"name":"Sabina María Maté","orcid":null,"position":4,"is_corresponding":false},{"id":1489562,"name":"M. Alejandra Tricerri","orcid":"0000-0002-6627-7999","position":5,"is_corresponding":false},{"id":1489563,"name":"Nahuel A. Ramella","orcid":"0000-0002-6275-3193","position":6,"is_corresponding":false},{"id":484343,"name":"Shimpi Bedi","orcid":"0000-0003-3277-7845","position":7,"is_corresponding":false},{"id":714872,"name":"Jamie Morris","orcid":null,"position":8,"is_corresponding":false},{"id":698803,"name":"Scott E Street","orcid":null,"position":9,"is_corresponding":false},{"id":1312109,"name":"Esmond Geh","orcid":"0000-0001-8492-2827","position":10,"is_corresponding":false},{"id":352735,"name":"Gérémy Clair","orcid":"0000-0003-0478-8520","position":11,"is_corresponding":false},{"id":304680,"name":"W. Sean Davidson","orcid":"0000-0003-2756-2989","position":12,"is_corresponding":false},{"id":698262,"name":"John Melchior","orcid":"0000-0003-3781-2566","position":13,"is_corresponding":false},{"id":1060816,"name":"Ivo Díaz Ludovico","orcid":"0000-0002-3475-5191","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41167396","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":[]}