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A topological switch in CFTR modulates channel activity and sensitivity to unfolding
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2021-08-02 , DOI: 10.1038/s41589-021-00844-0
Daniel Scholl 1 , Maud Sigoillot 1 , Marie Overtus 1 , Rafael Colomer Martinez 1 , Chloé Martens 1 , Yiting Wang 2 , Els Pardon 3, 4 , Toon Laeremans 3, 4 , Abel Garcia-Pino 5 , Jan Steyaert 3, 4 , David N Sheppard 2 , Jelle Hendrix 6, 7 , Cédric Govaerts 1
Affiliation  

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the β-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions.



中文翻译:

CFTR 中的拓扑开关调节通道活动和对展开的敏感性

囊性纤维化跨膜电导调节剂 (CFTR) 阴离子通道对于维持关键器官的液体稳态至关重要。由于cftr突变导致 CFTR 功能障碍基因导致囊性纤维化。在这里,我们表明 CFTR 的第一个核苷酸结合域 (NBD1) 可以自发地采用与先前观察到的规范 NBD 折叠不同的替代构象。晶体学显示这种构象涉及 NBD1 的拓扑重组。单分子荧光共振能量转移显微镜显示构象之间的平衡受三磷酸腺苷结合的调节。然而,在不稳定的条件下,例如致病突变 F508del,这种构象的灵活性使得 β-亚结构域能够展开。我们的数据表明,在野生型 CFTR 中,NBD1 的这种构象转变调节通道功能,但是,在存在 F508del 突变的情况下,它允许结构域错误折叠和随后的蛋白质降解。

更新日期:2021-08-02
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