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We have identified here the region responsible for this instability. Temperature-induced aggregation of C-terminally truncated versions of CFTR demonstrated that all truncations up to the second transmembrane domain (TMD2), including the R region, largely resisted aggregation. Limited proteolysis identified a folded structure that was prone to aggregation and consisted of TMD2 and at least part of the Regulatory Region R. Only when both TM7 (TransMembrane helix 7) and TM8 were present, TMD2 fragments became as aggregation-sensitive as wild-type CFTR, in line with increased thermo-instability of late CFTR nascent chains and in silico prediction of aggregation propensity. In accord, isolated TMD2 was degraded faster in cells than isolated TMD1. We conclude that TMD2 extended at its N-terminus with part of the R region forms a protease-resistant structure that induces heat instability in CFTR and may be responsible for its limited intracellular stability.<\/jats:p>","DOI":"10.3390\/ijms242115741","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T12:50:42Z","timestamp":1698670242000},"page":"15741","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Transmembrane Helices 7 and 8 Confer Aggregation Sensitivity to the Cystic Fibrosis Transmembrane Conductance Regulator"],"prefix":"10.3390","volume":"24","author":[{"given":"Bertrand","family":"Kleizen","sequence":"first","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"de Mattos","sequence":"additional","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Papaioannou","sequence":"additional","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Monti","sequence":"additional","affiliation":[{"name":"Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), 00161 Rome, Italy"},{"name":"Centre for Human Technologies (CHT), Istituto Italiano di Tecnologia (IIT), 16152 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gian Gaetano","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), 00161 Rome, Italy"},{"name":"Centre for Human Technologies (CHT), Istituto Italiano di Tecnologia (IIT), 16152 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4485-3342","authenticated-orcid":false,"given":"Peter","family":"van der Sluijs","sequence":"additional","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-4364","authenticated-orcid":false,"given":"Ineke","family":"Braakman","sequence":"additional","affiliation":[{"name":"Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2017","journal-title":"Nat. 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