Department of Chemistry, Faculty of Science, Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
PLoS One. 2010 Nov 30;5(11):e15458. doi: 10.1371/journal.pone.0015458.
In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues ΔF508 CFTR to the cell surface, but only I539T repaired ΔF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length ΔF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of ΔF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.
在绝大多数囊性纤维化（CF）患者中，CFTR 中残基 F508 的缺失是疾病的原因。F508 位于第一个核苷酸结合域（NBD1），其缺失导致 CFTR 错误折叠和降解。我们在这里表明，主要的折叠缺陷发生在合成过程中，一旦 NBD1 被翻译。在 NBD1 中引入 I539T 或 G550E 抑制突变部分挽救了 ΔF508 CFTR 到细胞表面，但只有 I539T 修复了 ΔF508 NBD1。我们证明了从细胞中表达的全长 ΔF508 CFTR 到分离纯化的结构域，NBD1 的折叠和稳定性的挽救。I539T 通过共翻译挽救 CFTR 中 ΔF508 NBD1 的错误折叠，这表明该结构域是囊性纤维化的最重要药物靶点。
