Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability

P. Andrew Chong, Pradeep Kota, Nikolay V. Dokholyan, Julie D. Forman-Kay

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) requires dynamic fluctuations between states in its gating cycle for proper channel function, including changes in the interactions between the nucleotide-binding domains (NBDs) and between the intracellular domain (ICD) coupling helices and NBDs. Such motions are also linked with fluctuating phosphorylation-dependent binding of CFTR's disordered regulatory (R) region to the NBDs and partners. Folding of CFTR is highly inefficient, with the marginally stable NBD1 sampling excited states or folding intermediates that are aggregation-prone. The severe CF- causing F508del mutation exacerbates the folding inefficiency of CFTR and leads to impaired channel regulation and function, partly as a result of perturbed NBD1-ICD interactions and enhanced sampling of these NBD1 excited states. Increased knowledge of the dynamics within CFTR will expand our understanding of the regulated channel gating of the protein as well as of the F508del defects in folding and function.

Original languageEnglish (US)
Article numbera009522
JournalCold Spring Harbor Perspectives in Medicine
Volume3
Issue number3
DOIs
StatePublished - Mar 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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