Biophysics Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA 94720, USA.
Science. 2019 Jan 4;363(6422):84-87. doi: 10.1126/science.aav6740. Epub 2018 Dec 13.
The Sec61 protein-conducting channel mediates transport of many proteins, such as secretory proteins, across the endoplasmic reticulum (ER) membrane during or after translation. Posttranslational transport is enabled by two additional membrane proteins associated with the channel, Sec63 and Sec62, but its mechanism is poorly understood. We determined a structure of the Sec complex (Sec61-Sec63-Sec71-Sec72) from by cryo-electron microscopy (cryo-EM). The structure shows that Sec63 tightly associates with Sec61 through interactions in cytosolic, transmembrane, and ER-luminal domains, prying open Sec61's lateral gate and translocation pore and thus activating the channel for substrate engagement. Furthermore, Sec63 optimally positions binding sites for cytosolic and luminal chaperones in the complex to enable efficient polypeptide translocation. Our study provides mechanistic insights into eukaryotic posttranslational protein translocation.
Sec61 蛋白转运通道在翻译过程中或翻译后介导许多蛋白质（如分泌蛋白）穿过内质网（ER）膜的转运。翻译后转运是通过与通道相关的另外两种膜蛋白 Sec63 和 Sec62 实现的，但该机制尚不清楚。我们通过冷冻电镜（cryo-EM）确定了来自 的 Sec 复合物（Sec61-Sec63-Sec71-Sec72）的结构。该结构表明，Sec63 通过与细胞质、跨膜和 ER 腔域的相互作用与 Sec61 紧密结合，撬开 Sec61 的侧向门和转运孔，从而激活通道以与底物结合。此外，Sec63 使复合物中细胞质和腔室伴侣的结合位点最佳定位，从而能够有效地进行多肽转运。我们的研究为真核翻译后蛋白转运提供了机制上的见解。
