Requirements for efficient correction of Δf508 CFTR revealed by analyses of evolved sequences

Juan L. Mendoza, André Schmidt, Qin Li, Emmanuel Nuvaga, Tyler Barrett, Robert J. Bridges, Andrew P Feranchak, Chad A Brautigam, Philip J Thomas

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)164-174
Number of pages11
JournalCell
Volume148
Issue number1-2
DOIs
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Mendoza, J. L., Schmidt, A., Li, Q., Nuvaga, E., Barrett, T., Bridges, R. J., Feranchak, A. P., Brautigam, C. A., & Thomas, P. J. (2012). Requirements for efficient correction of Δf508 CFTR revealed by analyses of evolved sequences. Cell, 148(1-2), 164-174. https://doi.org/10.1016/j.cell.2011.11.023