ArticleNature chemical biology2021
A topological switch in CFTR modulates channel activity and sensitivity to unfolding.
Article in Nature chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 23 citations in OpenAlex.
- Nanobody-mediated control of long RSH Rel and RelA catalysis by restriction of their conformational landscape.Nature communications · 2026Article
- Cryo-EM reveals a phosphorylated R-domain envelops the NBD1 catalytic domain in an ABC transporter.Life science alliance · 2024Article
- Photophysics in Biomembranes: Computational Insight into the Interaction between Lipid Bilayers and Chromophores.Accounts of chemical research · 2024Review
- Inhibition and transport mechanisms of the ABC transporter hMRP5.Nature communications · 2024Article
- Article
- CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine.ACS chemical biology · 2023Review
- Coupling of binding and differential subdomain folding of the intrinsically disordered transcription factor CREB.FEBS letters · 2023Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- Structural Comparative Modeling of Multi-Domain F508del CFTR.Biomolecules · 2022Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
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 β-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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.