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结构生物学揭示NEDD8介导的泛素组装机制
作者:小柯机器人 发布时间:2020/2/14 10:55:11

德国马克斯•普朗克学会生物化学研究所Brenda A. Schulman研究团队的一项最新研究,揭示了NEDD8介导的多价cullin-RING-UBE2D泛素连接组装机制。相关论文在线发表在2020年2月12日的《自然》上。

研究人员解析了一种化学捕获复合物的冷冻电镜结构,该复合物代表了泛素化的中间体,其中氨基化的cullin-RING E3连接酶(CRL1)β-TRCP促进泛素分子从E2泛素结合酶UBE2D转移至其募集的底物分子磷酸化IκBα上。NEDD8充当结合不同cullin元素和RING激活-泛素连接UBE2D的纽带。NEDD8的局部结构重塑与CRL结构域的大范围移动融合在一起,将底物和泛素化活性位点并置。这些发现解释了独特泛素样蛋白如何改变其靶标功能,并揭示了众多依赖NEDD8的蛋白是如何通过相互作用和构象变化以赋予CRL结构强大的催化活性,使其快速泛素化底物;其结构又脆弱 ,以实现cullin-RING蛋白的后续功能。

据悉,真核细胞的生物学特征依赖于cullin-RING E3连接酶(CRL)催化的蛋白泛素化,其受到泛素样蛋白NEDD8修饰的cullin精密调控。但是,CRL如何催化泛素化以及NEDD8激活机制仍然未知。

附:英文原文

Title: NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly

Author: Kheewoong Baek, David T. Krist, J. Rajan Prabu, Spencer Hill, Maren Klgel, Lisa-Marie Neumaier, Susanne von Gronau, Gary Kleiger, Brenda A. Schulman

Issue&Volume: 2020-02-12

Abstract: Eukaryotic cell biology depends on cullin–RING E3 ligase (CRL)-catalysed protein ubiquitylation1, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD82,3,4,5,6. However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1β-TRCP promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated IκBα. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin–RING proteins.

DOI: 10.1038/s41586-020-2000-y

Source: https://www.nature.com/articles/s41586-020-2000-y

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html