Structural Basis of an ERAD Pathway Mediated by the ER-Resident Protein Disulfide Reductase ERdj5
Structural Basis of an ERAD Pathway Mediated by the ER-Resident Protein Disulfide Reductase ERdj5
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DOI：
10.1016/j.molcel.2011.01.021
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发表时间：
2011-02-18
期刊：
影响因子：
16
通讯作者：
Inaba, Kenji
中科院分区：
文献类型：
--
作者：
Hagiwara, Masatoshi;Maegawa, Ken-ichi;Inaba, Kenji
ER相关降解（ERAD）是消除末端错误折叠蛋白质的ER质量控制过程。ERdj 5最近被发现是一个关键的ER-居民PDI家族成员蛋白，通过减少错误折叠的糖蛋白中被EDEM 1识别的不正确的二硫键来加速ERAD。我们在这里解决了全长ERdj 5的晶体结构，从而揭示ERdj 5包含N-末端J结构域和六个串联硫氧还蛋白结构域，可以分为N-和C-末端簇。我们的系统的生化分析表明，两个硫氧还蛋白结构域构成的C-末端簇形成高度还原平台，与EDEM 1相互作用，减少EDEM 1招募的底物，导致其促进降解。脉冲追踪实验进一步提供了直接证据，证明ERAD底物从钙连接蛋白顺序移动到下游EDEM 1-ERdj 5复合物，然后可能通过BiP移动到逆转运通道。我们提出了一个详细的分子观点ERdj 5如何介导ERAD与EDEM 1。
ER-associated degradation (ERAD) is an ER quality-control process that eliminates terminally misfolded proteins. ERdj5 was recently discovered to be a key ER-resident PDI family member protein that accelerates ERAD by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1. We here solved the crystal structure of full-length ERdj5, thereby revealing that ERdj5 contains the N-terminal J domain and six tandem thioredoxin domains that can be divided into the N- and C-terminal clusters. Our systematic biochemical analyses indicated that two thioredoxin domains that constitute the C-terminal cluster form the highly reducing platform that interacts with EDEM1 and reduces EDEM1-recruited substrates, leading to their facilitated degradation. The pulse-chase experiment further provided direct evidence for the sequential movement of an ERAD substrate from calnexin to the downstream EDEM1-ERdj5 complex, and then to the retrotranslocation channel, probably through BiP. We present a detailed molecular view of how ERdj5 mediates ERAD in concert with EDEM1.