Callebaut I, Eudes R, Mornon J-P, Lehn P
Systèmes moléculaires & Biologie structurale, LMCP, CNRS UMR7590, Universités Paris 6 & Paris 7, case 115, 4 place Jussieu, 75252 Paris Cedex 05, France.
Cell Mol Life Sci. 2004 Jan;61(2):230-42. doi: 10.1007/s00018-003-3386-z.
The cystic fibrosis transmembrane conductance regulator (CFTR) protein is encoded by the gene that is defective in cystic fibrosis, the most common lethal inherited disease among the Caucasian population. CFTR belongs to the ABC transporter superfamily, whose members form macromolecular architectures composed of two membrane-spanning domains and two nucleotide-binding domains (NBDs). The experimental structures of NBDs from several ABC transporters have recently been solved, opening new avenues for understanding the structure/function relationships and the consequences of some disease-causing mutations of CFTR. Based on a detailed sequence/structure analysis, we propose here a three-dimensional model of the human CFTR NBD heterodimer. This model, which is in agreement with recent experimental data, highlights the specific features of the CFTR asymmetric active sites located at the interface between the two NBDs. Moreover, additional CFTR-specific features can be identified at the subunit interface, which may play critical roles in active site interdependence and are uncommon in other NBD dimers.
囊性纤维化跨膜传导调节因子（CFTR）蛋白由导致囊性纤维化的基因编码，囊性纤维化是白种人群中最常见的致命性遗传疾病。CFTR属于ABC转运蛋白超家族，其成员形成由两个跨膜结构域和两个核苷酸结合结构域（NBDs）组成的大分子结构。最近已经解析了几种ABC转运蛋白NBDs的实验结构，为理解CFTR的结构/功能关系以及一些致病突变的后果开辟了新途径。基于详细的序列/结构分析，我们在此提出人CFTR NBD异二聚体的三维模型。该模型与最近的实验数据一致，突出了位于两个NBDs之间界面处的CFTR不对称活性位点的特定特征。此外，在亚基界面可以识别出其他CFTR特异性特征，这些特征可能在活性位点相互依赖性中起关键作用，并且在其他NBD二聚体中并不常见。
