英国MRC分子生物学实验室Ramanujan S. Hegde课题组的最新研究揭示多跨越膜蛋白的一种膜内伴侣机制。该研究于2022年10月19日在线发表于国际一流学术期刊《自然》。

研究人员对多跨越蛋白生物生成过程中的中间产物进行的生化和结构分析表明，新生的链没有与Sec61接触，后者被CCDC47闭锁并锁住。相反，Asterix与Sec61结合并将底物重定向到Sec61后面的一个位置，在那里PAT复合体有助于形成一个围绕着半封闭且充满脂质空腔的多跨越转接器。从核糖体中出现后，在这个空腔中检测到多个跨膜结构域（TMD），表明多跨越蛋白在Sec61后面插入和折叠。因此，几个多跨越蛋白的生物生成没有受到Sec61侧门抑制剂的阻碍。这些发现阐明了膜内伴侣的机制，并为内质网的多跨越膜蛋白生物生成提出了一个新的框架。

据了解，多跨越膜蛋白在生物学中发挥着众多作用，包括受体、转运体、离子通道和酶。多跨越蛋白是如何在内质网中共同翻译和折叠的，目前还不是很清楚。流行的模型认为，多跨越蛋白的每个TMD依次通过Sec61蛋白转运通道的前侧门进入脂质双分子层。PAT复合物是一种由Asterix和CCDC47组成的膜内伴侣，通过一种未知的机制与多跨越蛋白的早期TMD接触，从而促进其生物生成。

附：英文原文

Title: Mechanism of an intramembrane chaperone for multipass membrane proteins

Author: Smalinskait, Luka, Kim, Min Kyung, Lewis, Aaron J. O., Keenan, Robert J., Hegde, Ramanujan S.

Issue&Volume: 2022-10-19

Abstract: Multipass membrane proteins play numerous roles in biology and include receptors, transporters, ion channels and enzymes1,2. How multipass proteins are co-translationally inserted and folded at the endoplasmic reticulum is not well understood2. The prevailing model posits that each transmembrane domain (TMD) of a multipass protein successively passes into the lipid bilayer through a front-side lateral gate of the Sec61 protein translocation channel3,4,5,6,7,8,9. The PAT complex, an intramembrane chaperone comprising Asterix and CCDC47, engages early TMDs of multipass proteins to promote their biogenesis by an unknown mechanism10. Here, biochemical and structural analysis of intermediates during multipass protein biogenesis showed that the nascent chain is not engaged with Sec61, which is occluded and latched closed by CCDC47. Instead, Asterix binds to and redirects the substrate to a location behind Sec61, where the PAT complex contributes to a multipass translocon surrounding a semi-enclosed, lipid-filled cavity11. Detection of multiple TMDs in this cavity after their emergence from the ribosome suggests that multipass proteins insert and fold behind Sec61. Accordingly, biogenesis of several multipass proteins was unimpeded by inhibitors of the Sec61 lateral gate. These findings elucidate the mechanism of an intramembrane chaperone and suggest a new framework for multipass membrane protein biogenesis at the endopasmic reticulum.

DOI: 10.1038/s41586-022-05336-2

Source: https://www.nature.com/articles/s41586-022-05336-2