囊性纤维化跨膜电导调节子的原子结构。
Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator.
机构信息
The Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.
The Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, NY 10065, USA.
出版信息
Cell. 2016 Dec 1;167(6):1586-1597.e9. doi: 10.1016/j.cell.2016.11.014.
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from the ATP-binding cassette (ABC) transporter family. In this study, we determined the structure of zebrafish CFTR in the absence of ATP by electron cryo-microscopy to 3.7 Å resolution. Human and zebrafish CFTR share 55% sequence identity, and 42 of the 46 cystic-fibrosis-causing missense mutational sites are identical. In CFTR, we observe a large anion conduction pathway lined by numerous positively charged residues. A single gate near the extracellular surface closes the channel. The regulatory domain, dephosphorylated, is located in the intracellular opening between the two nucleotide-binding domains (NBDs), preventing NBD dimerization and channel opening. The structure also reveals why many cystic-fibrosis-causing mutations would lead to defects either in folding, ion conduction, or gating and suggests new avenues for therapeutic intervention.
囊性纤维化跨膜电导调节因子（CFTR）是一种阴离子通道，由 ATP 结合盒（ABC）转运蛋白家族进化而来。在这项研究中，我们通过电子冷冻显微镜在没有 ATP 的情况下将斑马鱼 CFTR 的结构解析至 3.7Å分辨率。人类和斑马鱼 CFTR 的序列同一性为 55%，46 个导致囊性纤维化的错义突变位点中有 42 个是相同的。在 CFTR 中，我们观察到一个由许多带正电荷的残基组成的大型阴离子传导途径。一个位于细胞外表面附近的单一门控关闭了通道。去磷酸化的调节域位于两个核苷酸结合域（NBD）之间的细胞内开口处，阻止 NBD 二聚化和通道开放。该结构还揭示了为什么许多导致囊性纤维化的突变会导致折叠、离子传导或门控缺陷，并为治疗干预提供了新的途径。
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