School of Biological Sciences, Faculty of Biology Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Biol Chem. 2019 Sep 25;400(10):1359-1370. doi: 10.1515/hsz-2018-0470.
Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette family of proteins because it has evolved into a channel. Mutations in CFTR cause cystic fibrosis, the most common genetic disease in people of European origin. The F508del mutation is found in about 90% of patients and here we present data that suggest its main effect is on CFTR stability rather than on the three-dimensional (3D) folded state. A survey of recent cryo-electron microscopy studies was carried out and this highlighted differences in terms of CFTR conformation despite similarities in experimental conditions. We further studied CFTR structure under various phosphorylation states and with the CFTR-interacting protein NHERF1. The coexistence of outward-facing and inward-facing conformations under a range of experimental conditions was suggested from these data. These results are discussed in terms of structural models for channel gating, and favour the model where the mostly disordered regulatory-region of the protein acts as a channel plug.
囊性纤维化跨膜电导调节因子（CFTR）是 ATP 结合盒蛋白家族中的一个独特成员，因为它已经进化成一种通道。CFTR 的突变导致囊性纤维化，这是欧洲裔人群中最常见的遗传疾病。F508del 突变约见于 90%的患者，我们在这里提供的数据表明，其主要作用是影响 CFTR 的稳定性，而不是三维（3D）折叠状态。对最近的冷冻电子显微镜研究进行了调查，这突出了尽管实验条件相似，但 CFTR 构象存在差异。我们进一步研究了在各种磷酸化状态下和与 CFTR 相互作用蛋白 NHERF1 存在下 CFTR 的结构。从这些数据中可以看出，在一系列实验条件下存在外向和内向构象的共存。这些结果根据通道门控的结构模型进行了讨论，并支持该模型，即该蛋白的大部分无序调节区域充当通道塞子。
