Istituto di Biofisica, Consiglio Nazionale delle Ricerche. Via De Marini, 6, 16149, Genova, Italy.
Sci Rep. 2020 May 21;10(1):8440. doi: 10.1038/s41598-020-65287-4.
One of the most common mutations in Cystic Fibrosis (CF) patients is the deletion of the amino acid phenylalanine at position 508. This mutation causes both the protein trafficking defect and an early degradation. Over time, small molecules, called correctors, capable of increasing the amount of mutated channel in the plasma membrane and causing an increase in its transport activity have been developed. This study shows that incubating in vitro cells permanently transfected with the mutated channel with the correctors VX809, VX661 and Corr4a, and the combination of VX809 and Corr4a, a recovery of anion transport activity is observed. Interestingly, the permeability of bicarbonate increases in the cells containing corrected p.F508del CFTR channels is greater than the increase of the halide permeability. These different increases of the permeability of bicarbonate and halides are consistent with the concept that the structural conformation of the pore of the corrector-rescued p.F508del channels would be different than the normal wild type CFTR protein.
在囊性纤维化 (CF) 患者中，最常见的突变之一是第 508 位氨基酸苯丙氨酸的缺失。这种突变导致蛋白转运缺陷和早期降解。随着时间的推移，已经开发出了一些称为校正剂的小分子，这些小分子能够增加突变通道在质膜中的数量，并增加其转运活性。本研究表明，用校正剂 VX809、VX661 和 Corr4a 以及 VX809 和 Corr4a 的组合孵育体外永久性转染突变通道的细胞，观察到阴离子转运活性的恢复。有趣的是，含有校正的 p.F508del CFTR 通道的细胞中碳酸氢盐通透性的增加大于卤化物通透性的增加。碳酸氢盐和卤化物通透性的这种不同增加与孔结构构象的概念一致，即校正剂拯救的 p.F508del 通道的结构构象不同于正常的野生型 CFTR 蛋白。
