Patrick Anna E, Thomas Philip J
Department of Physiology, University of Texas Southwestern Medical Center Dallas, TX, USA.
Front Pharmacol. 2012 Sep 6;3:162. doi: 10.3389/fphar.2012.00162. eCollection 2012.
Cystic fibrosis is a lethal genetic disease caused by lack of functional cystic fibrosis transmembrane conductance regulator (CFTR) proteins at the apical surface of secretory epithelia. CFTR is a multidomain protein, containing five domains, and its functional structure is attained in a hierarchical folding process. Most CF-causing mutations in CFTR, including the most common mutation, a deletion of phenylalanine at position 508 (ΔF508), are unable to properly fold into this functional native three dimensional structure. Currently, no high-resolution structural information about full length CFTR exists. However, insight has been gained through examining homologous ABC transporter structures, molecular modeling, and high-resolution structures of individual, isolated CFTR domains. Taken together, these studies indicate that the prevalent ΔF508 mutation disrupts two essential steps during the development of the native structure: folding of the first nucleotide binding domain (NBD1) and its later association with the fourth intracellular loop (ICL4) in the second transmembrane domain (TMD2). Therapeutics to rescue ΔF508 and other mutants in CFTR can be targeted to correct defects that occur during the complex folding process. This article reviews the structural relationships between CFTR and ABC transporters and current knowledge about how CFTR attains its structure-with a focus on how this process is altered by CF-causing mutations in a manner targetable by therapeutics.
囊性纤维化是一种致命的遗传性疾病，由分泌上皮顶端表面缺乏功能性囊性纤维化跨膜传导调节因子（CFTR）蛋白所致。CFTR是一种多结构域蛋白，包含五个结构域，其功能结构在一个分级折叠过程中形成。CFTR中大多数导致CF的突变，包括最常见的突变——第508位苯丙氨酸缺失（ΔF508），都无法正确折叠成这种功能性天然三维结构。目前，尚无关于全长CFTR的高分辨率结构信息。然而，通过研究同源ABC转运蛋白结构、分子建模以及单个分离的CFTR结构域的高分辨率结构，已经获得了一些见解。综合这些研究表明，普遍存在的ΔF508突变在天然结构形成过程中破坏了两个关键步骤：第一个核苷酸结合结构域（NBD1）的折叠及其随后与第二个跨膜结构域（TMD2）中的第四个细胞内环（ICL4）的结合。拯救CFTR中ΔF508及其他突变体的疗法可以针对纠正复杂折叠过程中出现的缺陷。本文综述了CFTR与ABC转运蛋白之间的结构关系以及目前关于CFTR如何形成其结构的知识——重点关注该过程如何因导致CF的突变而改变，而这种改变可以通过治疗手段加以靶向纠正。
