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人类 ERAD 逆行转运复合物的冷冻电镜结构。

The cryo-EM structure of the human ERAD retrotranslocation complex.

机构信息

Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Shanghai 200125, China.

出版信息

Sci Adv. 2023 Oct 13;9(41):eadi5656. doi: 10.1126/sciadv.adi5656.

Abstract

Endoplasmic reticulum-associated degradation (ERAD) maintains protein homeostasis by retrieving misfolded proteins from the endoplasmic reticulum (ER) lumen into the cytosol for degradation. The retrotranslocation of misfolded proteins across the ER membrane is an energy-consuming process, with the detailed transportation mechanism still needing clarification. We determined the cryo-EM structures of the hetero-decameric complex formed by the Derlin-1 tetramer and the p97 hexamer. It showed an intriguing asymmetric complex and a putative coordinated squeezing movement in Derlin-1 and p97 parts. With the conformational changes of p97 induced by its ATP hydrolysis activities, the Derlin-1 channel could be torn into a "U" shape with a large opening to the lipidic environment, thereby forming an entry for the substrates in the ER membrane. The EM analysis showed that p97 formed a functional protein complex with Derlin-1, revealing the coupling mechanism between the ERAD retrotranslocation and the ATP hydrolysis activities.

摘要

内质网相关降解(ERAD)通过将内质网(ER)腔中的错误折叠蛋白回收到细胞质中进行降解,从而维持蛋白质的动态平衡。错误折叠蛋白跨 ER 膜的反向易位是一个耗能过程,其详细的运输机制仍需要阐明。我们确定了由 Derlin-1 四聚体和 p97 六聚体形成的异源二十聚体复合物的冷冻电镜结构。它显示了一个有趣的不对称复合物和 Derlin-1 和 p97 部分的假定协调挤压运动。随着 p97 的构象变化由其 ATP 水解活性诱导,Derlin-1 通道可以被撕裂成一个“U”形,与脂质环境的开口较大,从而为 ER 膜中的底物形成一个入口。EM 分析表明,p97 与 Derlin-1 形成了一个功能蛋白复合物,揭示了 ERAD 反向易位与 ATP 水解活性之间的偶联机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fd7/10575581/6ee823df06d1/sciadv.adi5656-f1.jpg

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