Stabilizing Rescued Surface-Localized 螖F508 CFTR by Potentiation of Its Interaction with Na+/H+ Exchanger Regulatory Factor 1

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• 作者：Kavisha Arora ; Changsuk Moon ; Weiqiang Zhang ; Sunitha Yarlagadda ; Himabindu Penmatsa ; Aixia Ren ; Chandrima Sinha ; Anjaparavanda P. Naren
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：July 1, 2014
• 年：2014
• 卷：53
• 期：25
• 页码：4169-4179
• 全文大小：561K
• ISSN：1520-4995

文摘

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in CFTR, a plasma-membrane-localized anion channel. The most common mutation in CFTR, deletion of phenylalanine at residue 508 (螖F508), causes misfolding of CFTR resulting in little or no protein at the plasma membrane. The CFTR corrector VX-809 shows promise for treating CF patients homozygous for 螖F508. Here, we demonstrate the significance of protein鈥損rotein interactions in enhancing the stability of the 螖F508 CFTR mutant channel protein at the plasma membrane. We determined that VX-809 prolongs the stability of 螖F508 CFTR at the plasma membrane. Using competition-based assays, we demonstrated that 螖F508 CFTR interacts poorly with Na⁺/H⁺ exchanger regulatory factor 1 (NHERF1) compared to wild-type CFTR, and VX-809 significantly increased this binding affinity. We conclude that stabilized CFTR鈥揘HERF1 interaction is a determinant of the functional efficiency of rescued 螖F508 CFTR. Our results demonstrate the importance of macromolecular-complex formation in stabilizing rescued mutant CFTR at the plasma membrane and suggest this to be foundational for the development of a new generation of effective CFTR-corrector-based therapeutics.