ArticleThe Journal of biological chemistry
The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Profiling the CFTR Variant Selectivity and Off-Target Interactions of VX-121.bioRxiv : the preprint server for biology · 2026Article
- Barriers to the Pharmacologic Rescue of W1282X CFTR.Biochemistry · 2026Article
- Personalized Medicine in Cystic Fibrosis: Characterization of Eight Rare CFTR Variants in Intestinal Organoids and Cellular Models.Molecular diagnosis & therapy · 2026Article
- General trends in the calnexin-dependent expression and pharmacological rescue of clinical CFTR variants.eLife · 2025Article
- General Trends in the Calnexin-Dependent Expression and Pharmacological Rescue of Clinical CFTR Variants.bioRxiv : the preprint server for biology · 2025Article
- Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases.Israel journal of chemistry · 2024Article
- COPII cage assembly factor Sec13 integrates information flow regulating endomembrane function in response to human variation.Scientific reports · 2024Article
- A uniquely efficacious type of CFTR corrector with complementary mode of action.Science advances · 2024Article
- Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.Nature communications · 2023Article
- CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine.ACS chemical biology · 2023Review
- Structural Insights into ATP-Sensitive Potassium Channel Mechanics: A Role of Intrinsically Disordered Regions.Journal of chemical information and modeling · 2023Article
- Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics.bioRxiv : the preprint server for biology · 2023Article
- Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.International journal of molecular sciences · 2022Article
- Triangulating variation in the population to define mechanisms for precision management of genetic disease.Structure (London, England : 1993) · 2022Article
- Molecular Dynamics and Theratyping in Airway and Gut Organoids Reveal R352Q-CFTR Conductance Defect.American journal of respiratory cell and molecular biology · 2022Article
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- Distinct proteostasis states drive pharmacologic chaperone susceptibility for cystic fibrosis transmembrane conductance regulator misfolding mutants.Molecular biology of the cell · 2022Article
- Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity.iScience · 2022Article
- S945L-CFTR molecular dynamics, functional characterization and tezacaftor/ivacaftor efficacyFrontiers in pediatrics · 2022Article
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Authors and funding
10 authors.
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Abstract
Patients with cystic fibrosis (CF) harboring the P67L variant in the cystic fibrosis transmembrane conductance regulator (CFTR) often exhibit a typical CF phenotype, including severe respiratory compromise. This rare mutation (reported in <300 patients worldwide) responds robustly to CFTR correctors, such as lumacaftor and tezacaftor, with rescue in model systems that far exceed what can be achieved for the archetypical CFTR mutant F508del. However, the specific molecular consequences of the P67L mutation are poorly characterized. In this study, we conducted biochemical measurements following low-temperature growth and/or intragenic suppression, which suggest a mechanism underlying P67L that (1) shares key pathogenic features with F508del, including off-pathway (non-native) folding intermediates, (2) is linked to folding stability of nucleotide-binding domains 1 and 2, and (3) demonstrates pharmacologic rescue that requires domains in the carboxyl half of the protein. We also investigated the "lasso" helices 1 and 2, which occur immediately upstream of P67. Based on limited proteolysis, pulse chase, and molecular dynamics analysis of full-length CFTR and a series of deletion constructs, we argue that P67L and other maturational processing (class 2) defects impair the integrity of the lasso motif and confer misfolding of downstream domains. Thus, amino-terminal missense variants elicit a conformational change throughout CFTR that abrogates maturation while providing a robust substrate for pharmacologic repair.
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