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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:p>Cystic fibrosis is a lethal genetic disorder caused by misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, most commonly due to the \u0394F508 mutation. Despite extensive study, CFTR\u2019s folding process has remained inaccessible to direct observation. Here, we apply single-molecule magnetic tweezers to resolve the complete folding trajectories of wild-type and \u0394F508 CFTR with near\u2013amino acid resolution. We find that CFTR follows a hierarchical, template-guided folding pathway in which N-terminal domains scaffold downstream folding. This mechanism tightly couples the free energy states of intermediates, allowing \u0394F508-induced instability to propagate across the folding pathway. Pharmacological correctors, in synergy with ATP, reshape the entire folding energy landscape by catalyzing transitions rather than simply stabilizing end states. These long-range, allosteric effects reveal a folding-embedded regulatory network. Our work provides a quantitative framework for mapping multidomain protein folding and therapeutic rescue, offering a broadly applicable strategy for interrogating rare mutations and accelerating structure-based drug discovery.<\/jats:p>","DOI":"10.1073\/pnas.2528216123","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T18:01:31Z","timestamp":1774980091000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Single-molecule dissection of CFTR folding defects and pharmacological rescue"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-5851","authenticated-orcid":false,"given":"Sang Ah","family":"Kim","sequence":"first","affiliation":[{"name":"School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8916-4241","authenticated-orcid":false,"given":"Jesper","family":"Levring","sequence":"additional","affiliation":[{"name":"Laboratory of Membrane Biology and Biophysics, The Rockefeller University","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2075-4283","authenticated-orcid":false,"given":"Jue","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Membrane Biology and Biophysics, The Rockefeller University","place":["New York"]},{"name":"HHMI","place":["Chevy Chase"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Young","family":"Yoon","sequence":"additional","affiliation":[{"name":"School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University","place":["Seoul, South Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90155-6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90072-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1704151"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90398-X"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.014"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(99)00163-7"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcl.2016.04.001"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04712"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ge.29.120195.004021"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra043184"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990318"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.103004.142532"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1999.79.1.S167"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.131623"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.024"},{"key":"e_1_3_4_18_2","article-title":"A review of Trikafta: Triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy","volume":"13","author":"Zaher A.","year":"2021","unstructured":"A. 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