ArticleProtein science : a publication of the Protein Society2010
Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1.
Article in Protein science : a publication of the Protein Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed, 133 citations in OpenAlex.
- ATP-dependent thermoring basis for the heat unfolding of the first nucleotide-binding domain isolated from human CFTR.Research square · 2024Article
- Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants.bioRxiv : the preprint server for biology · 2024Article
- Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants.PloS one · 2024Article
- CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine.ACS chemical biology · 2023Review
- Acting on the CFTR Membrane-Spanning Domains Interface Rescues Some Misfolded Mutants.International journal of molecular sciences · 2022Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives.Journal of medicinal chemistry · 2022Review
- Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold.Communications biology · 2022Article
- Structural Comparative Modeling of Multi-Domain F508del CFTR.Biomolecules · 2022Article
- Systematic evaluation of computational tools to predict the effects of mutations on protein stability in the absence of experimental structures.Briefings in bioinformatics · 2022Article
- A small molecule high throughput screening platform to profile conformational properties of nascent, ribosome-bound proteins.Scientific reports · 2022Article
- Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1.Computational and structural biotechnology journal · 2022Article
- Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.Cellular and molecular life sciences : CMLS · 2021Article
- A topological switch in CFTR modulates channel activity and sensitivity to unfolding.Nature chemical biology · 2021Article
- Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.Journal of chemical information and modeling · 2021Article
- Stability of the Retinoid X Receptor-α Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide.Biochemistry · 2021Article
- New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.Scientific reports · 2021Article
- CFTR trafficking mutations disrupt cotranslational protein folding by targeting biosynthetic intermediates.Nature communications · 2020Article
- Factoring in the Complexity of the Cystic Fibrosis Lung to UnderstandPathogens (Basel, Switzerland) · 2020Review
- ATP-dependent thermostabilization of human P-glycoprotein (ABCB1) is blocked by modulators.The Biochemical journal · 2019Article
14 more citing papers are in PubMed but not listed here.
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9 authors at 4 institutions in 1 country.
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Abstract
Misfolding and degradation of CFTR is the cause of disease in patients with the most prevalent CFTR mutation, an in-frame deletion of phenylalanine (F508del), located in the first nucleotide-binding domain of human CFTR (hNBD1). Studies of (F508del)CFTR cellular folding suggest that both intra- and inter-domain folding is impaired. (F508del)CFTR is a temperature-sensitive mutant, that is, lowering growth temperature, improves both export, and plasma membrane residence times. Yet, paradoxically, F508del does not alter the fold of isolated hNBD1 nor did it seem to perturb its unfolding transition in previous isothermal chemical denaturation studies. We therefore studied the in vitro thermal unfolding of matched hNBD1 constructs ±F508del to shed light on the defective folding mechanism and the basis for the thermal instability of (F508del)CFTR. Using primarily differential scanning calorimetry (DSC) and circular dichroism, we show for all hNBD1 pairs studied, that F508del lowers the unfolding transition temperature (T(m)) by 6-7°C and that unfolding occurs via a kinetically-controlled, irreversible transition in isolated monomers. A thermal unfolding mechanism is derived from nonlinear least squares fitting of comprehensive DSC data sets. All data are consistent with a simple three-state thermal unfolding mechanism for hNBD1 ± F508del: N(±MgATP) <==> I(T)(±MgATP) → A(T) → (A(T))(n). The equilibrium unfolding to intermediate, I(T), is followed by the rate-determining, irreversible formation of a partially folded, aggregation-prone, monomeric state, A(T), for which aggregation to (A(T))(n) and further unfolding occur with no detectable heat change. Fitted parameters indicate that F508del thermodynamically destabilizes the native state, N, and accelerates the formation of A(T).
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