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http://hdl.handle.net/1942/34721
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DC Field | Value | Language |
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dc.contributor.author | Scholl, Daniel | - |
dc.contributor.author | Sigoillot, Maud | - |
dc.contributor.author | Overtus, Marie | - |
dc.contributor.author | Martinez, Rafael Colomer | - |
dc.contributor.author | Martens, Chloe | - |
dc.contributor.author | Wang, Yiting | - |
dc.contributor.author | Pardon, Els | - |
dc.contributor.author | Laeremans, Toon | - |
dc.contributor.author | Garcia-Pino, Abel | - |
dc.contributor.author | Steyaert, Jan | - |
dc.contributor.author | Sheppard, David N. | - |
dc.contributor.author | HENDRIX, Jelle | - |
dc.contributor.author | Govaerts, Cedric | - |
dc.date.accessioned | 2021-08-28T17:38:04Z | - |
dc.date.available | 2021-08-28T17:38:04Z | - |
dc.date.issued | 2021 | - |
dc.date.submitted | 2021-08-27T18:11:20Z | - |
dc.identifier.citation | Nature chemical biology, 17 (9) , p. 989-997 | - |
dc.identifier.issn | 1552-4450 | - |
dc.identifier.uri | http://hdl.handle.net/1942/34721 | - |
dc.description.abstract | The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the beta-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions. | - |
dc.description.sponsorship | Fonds Forton, Welbio [CR-2012S-04R]; Vaincre la Mucoviscidose, Mukoviszidose e.V; Association Luxembourgeoise de Lutte contre la Mucoviscidose; ABCF2; Chiesi FondationChiesi Pharmaceuticals Inc; Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation; Fibrosis FoundationItalian Cystic Fibrosis Research Foundation; [BB/M012573/1]; CF Foundation Therapeutics; Instruct-ERIC, part of the European Strategy Forum on Research Infrastructures (ESFRI); Instruct-ULTRA 731005; FWO | - |
dc.language.iso | en | - |
dc.publisher | NATURE PORTFOLIO | - |
dc.rights | The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 | - |
dc.title | A topological switch in CFTR modulates channel activity and sensitivity to unfolding | - |
dc.type | Journal Contribution | - |
dc.identifier.epage | 997 | - |
dc.identifier.issue | 9 | - |
dc.identifier.spage | 989 | - |
dc.identifier.volume | 17 | - |
local.format.pages | 22 | - |
local.bibliographicCitation.jcat | A1 | - |
dc.description.notes | Govaerts, C (corresponding author), Univ Libre Bruxelles, SFMB, Brussels, Belgium. | - |
dc.description.notes | Cedric.Govaerts@ulb.ac.be | - |
local.publisher.place | HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY | - |
local.type.refereed | Refereed | - |
local.type.specified | Article | - |
dc.identifier.doi | 10.1038/s41589-021-00844-0 | - |
dc.identifier.isi | WOS:000680383200003 | - |
dc.contributor.orcid | Pardon, Els/0000-0002-2466-0172; Steyaert, Jan/0000-0002-3825-874X | - |
dc.identifier.eissn | 1552-4469 | - |
local.provider.type | wosris | - |
local.uhasselt.uhpub | yes | - |
local.description.affiliation | [Scholl, Daniel; Sigoillot, Maud; Overtus, Marie; Martinez, Rafael Colomer; Martens, Chloe; Govaerts, Cedric] Univ Libre Bruxelles, SFMB, Brussels, Belgium. | - |
local.description.affiliation | [Wang, Yiting; Sheppard, David N.] Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol, Avon, England. | - |
local.description.affiliation | [Pardon, Els; Laeremans, Toon; Steyaert, Jan] VIB, VIB VUB Ctr Struct Biol, Brussels, Belgium. | - |
local.description.affiliation | [Pardon, Els; Laeremans, Toon; Steyaert, Jan] Vrije Univ Brussel, Struct Biol Brussels, Brussels, Belgium. | - |
local.description.affiliation | [Garcia-Pino, Abel] Univ Libre Bruxelles, Cellular & Mol Microbiol, Gosselies, Belgium. | - |
local.description.affiliation | [Hendrix, Jelle] Hasselt Univ, Adv Opt Microscopy Ctr, Dynam Bioimaging Lab, Diepenbeek, Belgium. | - |
local.description.affiliation | [Hendrix, Jelle] Hasselt Univ, Biomed Res Inst, Diepenbeek, Belgium. | - |
local.description.affiliation | [Hendrix, Jelle] Katholieke Univ Leuven, Chem Dept, Mol Imaging & Photon, Leuven, Belgium. | - |
local.uhasselt.international | yes | - |
item.fullcitation | Scholl, Daniel; Sigoillot, Maud; Overtus, Marie; Martinez, Rafael Colomer; Martens, Chloe; Wang, Yiting; Pardon, Els; Laeremans, Toon; Garcia-Pino, Abel; Steyaert, Jan; Sheppard, David N.; HENDRIX, Jelle & Govaerts, Cedric (2021) A topological switch in CFTR modulates channel activity and sensitivity to unfolding. In: Nature chemical biology, 17 (9) , p. 989-997. | - |
item.validation | ecoom 2022 | - |
item.accessRights | Open Access | - |
item.fulltext | With Fulltext | - |
item.contributor | Scholl, Daniel | - |
item.contributor | Sigoillot, Maud | - |
item.contributor | Overtus, Marie | - |
item.contributor | Martinez, Rafael Colomer | - |
item.contributor | Martens, Chloe | - |
item.contributor | Wang, Yiting | - |
item.contributor | Pardon, Els | - |
item.contributor | Laeremans, Toon | - |
item.contributor | Garcia-Pino, Abel | - |
item.contributor | Steyaert, Jan | - |
item.contributor | Sheppard, David N. | - |
item.contributor | HENDRIX, Jelle | - |
item.contributor | Govaerts, Cedric | - |
crisitem.journal.issn | 1552-4450 | - |
crisitem.journal.eissn | 1552-4469 | - |
Appears in Collections: | Research publications |
Files in This Item:
File | Description | Size | Format | |
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s41589-021-00844-0.pdf Restricted Access | Published version | 9.9 MB | Adobe PDF | View/Open Request a copy |
Scholl_et_al_Nat_Chem_Biol_2021_accepted_text_figures.pdf | Peer-reviewed author version | 63.65 MB | Adobe PDF | View/Open |
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