CFTR trafficking mutations disrupt cotranslational protein folding by targeting biosynthetic intermediates.
CFTR trafficking mutations disrupt cotranslational protein folding by targeting biosynthetic intermediates.
复制标题
CFTR 运输突变通过靶向生物合成中间体来破坏共翻译蛋白折叠。
DOI：
10.1038/s41467-020-18101-8
复制
发表时间：
2020
影响因子：
16.6
通讯作者：
Skach,WilliamR
中科院分区：
文献类型：
--
作者：
Shishido,Hideki;Yoon,JaeSeok;Yang,Zhongying;Skach,WilliamR
蛋白质错误折叠导致广泛的人类疾病，靶向错误折叠的治疗正在改变囊性纤维化的临床护理。然而，尽管取得了这一成功，人们对致病突变如何影响从头折叠景观知之甚少。在这里，我们表明位于囊性纤维化跨膜传导调节因子（CFTR）的第一个核苷酸结合结构域（NBD 1）内的遗传性致病突变对新生多肽具有明显的影响。这些突变中的两个（A455E和L558S）在合成的关键窗口期间延迟新生NBD 1的压缩。观察到的折叠缺陷高度依赖于新生链长度以及其与核糖体的附着。此外，通过第二位点抑制突变恢复NBD1共翻译折叠缺陷也部分恢复全长CFTR的折叠。这些发现表明，新生折叠中间体可以在疾病的发病机制中发挥重要作用，从而提供潜在的药物校正的目标。
Protein misfolding causes a wide spectrum of human disease, and therapies that target misfolding are transforming the clinical care of cystic fibrosis. Despite this success, however, very little is known about how disease-causing mutations affect the de novo folding landscape. Here we show that inherited, disease-causing mutations located within the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) have distinct effects on nascent polypeptides. Two of these mutations (A455E and L558S) delay compaction of the nascent NBD1 during a critical window of synthesis. The observed folding defect is highly dependent on nascent chain length as well as its attachment to the ribosome. Moreover, restoration of the NBD1 cotranslational folding defect by second site suppressor mutations also partially restores folding of full-length CFTR. These findings demonstrate that nascent folding intermediates can play an important role in disease pathogenesis and thus provide potential targets for pharmacological correction.