美国哈佛医学院Tom A. Rapoport小组在研究中取得进展。他们揭示了Hrd1泛素连接酶复合物介导内质网（ER）相关蛋白降解的结构基础。相关论文于2020年4月24日发表在《科学》杂志上。

研究人员通过两个亚复合物的冷冻电镜分析解析了活性Hrd1复合物的结构。Hrd3和Yos9共同构成了一个可识别糖基化底物的腔结合位点。Hrd1和类菱形Der1蛋白形成两个“半通道”，分别具有胞质腔和内腔，并且在薄膜区域侧向通道门中彼此相对。

这些结构以及交联和分子动力学模拟共同证明了ER相关降解（ERAD-L）底物的多肽环是如何移动穿过ER膜的。

据介绍，错误折叠的内质网腔蛋白由ERAD-L途径降解，它们被逆向转运到细胞质中，多泛素化后被蛋白酶体降解。ERAD-L是由Hrd1复合体（由Hrd1、Hrd3、Der1、Usa1和Yos9组成）介导的，但其逆转座机制仍然是未知的。

附：英文原文

Title: Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex

Author: Xudong Wu, Marc Siggel, Sergey Ovchinnikov, Wei Mi, Vladimir Svetlov, Evgeny Nudler, Maofu Liao, Gerhard Hummer, Tom A. Rapoport

Issue&Volume: 2020/04/24

Abstract: Misfolded luminal endoplasmic reticulum (ER) proteins undergo ER-associated degradation (ERAD-L): They are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex (composed of Hrd1, Hrd3, Der1, Usa1, and Yos9), but the mechanism of retrotranslocation remains mysterious. Here, we report a structure of the active Hrd1 complex, as determined by cryo–electron microscopy analysis of two subcomplexes. Hrd3 and Yos9 jointly create a luminal binding site that recognizes glycosylated substrates. Hrd1 and the rhomboid-like Der1 protein form two “half-channels” with cytosolic and luminal cavities, respectively, and lateral gates facing one another in a thinned membrane region. These structures, along with crosslinking and molecular dynamics simulation results, suggest how a polypeptide loop of an ERAD-L substrate moves through the ER membrane.

DOI: 10.1126/science.aaz2449

Source: https://science.sciencemag.org/content/368/6489/eaaz2449