Requirements for Efficient Correction of ΔF508 CFTR Revealed by Analyses of Evolved Sequences

Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules th...

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Bibliographic Details
Published in:	Cell Vol. 148; no. 1-2; pp. 164 - 174
Main Authors:	Mendoza, Juan L., Schmidt, André, Li, Qin, Nuvaga, Emmanuel, Barrett, Tyler, Bridges, Robert J., Feranchak, Andrew P., Brautigam, Chad A., Thomas, Philip J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 20-01-2012
Subjects:	Animals ATP-Binding Cassette Transporters - chemistry ATP-Binding Cassette Transporters - metabolism cystic fibrosis Cystic Fibrosis - genetics Cystic Fibrosis - therapy Cystic Fibrosis Transmembrane Conductance Regulator - chemistry Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism defects Humans Mice Models, Molecular mutation patients Protein Folding Protein Structure, Tertiary Suppression, Genetic
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Summary:	Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps. [Display omitted] ► Statistical coupling analyses reveal positions linked to F508 ► Coupled positions reveal that the ΔF508 mutation interferes with two steps in CFTR folding ► Two defects of ΔF508 misfolding explain the efficacy ceiling observed for correctors ► Correction of both defective steps is synergistic and required to restore function ΔF508 CFTR surface expression and function are corrected by bothcounteracting the misfolding of the first nucleotide-binding domain (NBD1) and restoring its interaction with the fourth intracellular loop (ICL4), explaining the efficacy ceiling of corrector molecule therapies that only correct the folding defect.
Bibliography:	http://dx.doi.org/10.1016/j.cell.2011.11.023
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2011.11.023