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Article Dans Une Revue Journal of Cystic Fibrosis Année : 2022

Structure basis of CFTR folding, function and pharmacology

Résumé

The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.
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Dates et versions

hal-03838359 , version 1 (03-11-2022)

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Tzyh-Chang Hwang, Ineke Braakman, Peter van der Sluijs, Isabelle Callebaut. Structure basis of CFTR folding, function and pharmacology. Journal of Cystic Fibrosis, 2022, ⟨10.1016/j.jcf.2022.09.010⟩. ⟨hal-03838359⟩
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