Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane
Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane
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DOI：
10.1038/ncb2882
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发表时间：
2014-01-01
影响因子：
21.3
通讯作者：
Jarosch, Ernst
中科院分区：
文献类型：
--
作者：
Mehnert, Martin;Sommer, Thomas;Jarosch, Ernst
从内质网 (ER) 中提取分泌途径的错误折叠蛋白，通过称为 Hmg-CoA 还原酶降解连接酶 (HRD 连接酶) 的蛋白复合物进行多泛素化，并通过胞质 26S 蛋白酶体进行降解。这些蛋白质通过脂质双层的运动被认为是通过性质未知的蛋白质传导通道发生的。我们发现整合膜蛋白 Der1 寡聚化，这依赖于其与支架蛋白 Usa1 的相互作用。 Der1 跨膜结构域的突变阻止可溶性蛋白穿过 ER 膜。通过位点特异性光交联测定，Den I 的 ER 管腔暴露部分在空间上邻近底物受体 Hrd3，而膜嵌入结构域则邻近泛素连接酶 Hrd1。有趣的是，这两个区域也与客户蛋白形成交联。我们的数据表明，Der1 通过将异常多肽穿入 ER 膜并将其路由至 Hrd1 进行泛素化，从而启动异常多肽从 ER 腔的输出。
Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD ligase) and degraded by cytosolic 26S proteasomes. The movement of these proteins through the lipid bilayer is assumed to occur via a protein-conducting channel of unknown nature. We show that the integral membrane protein Der1 oligomerizes, which relies on its interaction with the scaffolding protein Usa1. Mutations in the transmembrane domains of Der1 block the passage of soluble proteins across the ER membrane. As determined by site-specific photocrosslinking, the ER-luminal exposed parts of Den l are in spatial proximity to the substrate receptor Hrd3, whereas the membrane-embedded domains reside adjacent to the ubiquitin ligase Hrd1. Intriguingly, both regions also form crosslinks to client proteins. Our data imply that Der1 initiates the export of aberrant polypeptides from the ER lumen by threading such molecules into the ER membrane and routing them to Hrd1 for ubiquitylation.