Seibert F S, Loo T W, Clarke D M, Riordan J R
Department of Medicine, University of Toronto, Ontario, Canada.
J Bioenerg Biomembr. 1997 Oct;29(5):429-42. doi: 10.1023/a:1022478822214.
The identification and characterization of the CFTR gene and protein have provided not only a major impetus to the dissection of the molecular pathophysiology of cystic fibrosis (CF) but also a new perspective on the structure and function of the large superfamily of membrane transport proteins to which it belongs. While the mechanism of the active vectorial translocation of many hydrophobic substrates by several of these transporters remains nearly as perplexing as it has for several decades, considerable insight has been gained into the control of the bidirectional permeation of chloride ions through a single CFTR channel by the phosphorylation of the R-domain and ATP interactions at the two nucleotide binding domains. However, details of these catalytic and allosteric mechanisms remain to be elucidated and await the replacement of two-dimensional conceptualizations with three dimensional structure information. Secondary and tertiary structure determination is required both for the understanding of the mechanism of action of the molecule and to enable a more complete appreciation of the misfolding and misprocessing of mutant CFTR molecules. This is the primary cause of the disease in the majority of the patients and hence understanding the details of the cotranslational interactions with multiple molecular chaperones, the ubiquitin-proteasome pathway and other components of the quality control machinery at the endoplasmic reticulum could provide a basis for the development of new therapeutic interventions.
囊性纤维化跨膜传导调节因子（CFTR）基因和蛋白质的鉴定与特性分析，不仅极大推动了对囊性纤维化（CF）分子病理生理学的剖析，还为其所属的膜转运蛋白大型超家族的结构与功能提供了新视角。尽管其中一些转运蛋白对许多疏水性底物进行主动向量转运的机制，几十年来几乎一直令人困惑，但通过R结构域的磷酸化以及两个核苷酸结合结构域处的ATP相互作用，我们对氯离子通过单个CFTR通道的双向渗透控制已获得了相当多的见解。然而，这些催化和变构机制的细节仍有待阐明，并且需要用三维结构信息取代二维概念。为了理解该分子的作用机制，并更全面地认识突变CFTR分子的错误折叠和错误加工，需要确定其二级和三级结构。这是大多数患者发病的主要原因，因此，了解与多种分子伴侣的共翻译相互作用细节、泛素-蛋白酶体途径以及内质网质量控制机制的其他组成部分，可为开发新的治疗干预措施提供依据。
