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CUL5-ARIH2 E3-E3 泛素连接酶结构揭示了连接酶的特异性 NEDD8 激活。

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation.

机构信息

Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.

Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.

出版信息

Nat Chem Biol. 2021 Oct;17(10):1075-1083. doi: 10.1038/s41589-021-00858-8. Epub 2021 Sep 13.

DOI:10.1038/s41589-021-00858-8
PMID:34518685
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8460447/
Abstract

An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.

摘要

一种新兴的泛素化机制涉及两种不同 E3 连接酶的配对。在研究最充分的 E3-E3 途径中，ARIH 家族 RING 之间 RING（RBR）E3 将泛素连接到 neddylated 环结构域 RING 型 E3 的底物上。E3 ARIH2 已被牵连到 neddylated CUL5-RBX2 为基础的 E3 的底物的泛素化，包括 HIV-1 病毒感染因子（Vif）劫持的宿主 E3 的 APOBEC3 家族底物。然而，结构机制仍然难以捉摸。这里的结构和生化分析揭示了独特的 ARIH2 自动抑制，以及与 neddylated CUL5-RBX2 组装时的激活。与包括 ARIH1 和 neddylated CUL1-RBX1 为基础的 E3 的 E3-E3 组装结构的比较表明，NEDD8 对 cullin 具有特异性调节。虽然 CUL1 连接的 NEDD8 直接招募 ARIH1，但 CUL5 连接的 NEDD8 不与 ARIH2 结合。相反，数据显示了一种变构机制。NEDD8 独特地接触共价连接的 CUL5，并引发结构重排，揭示出隐藏的 ARIH2 结合位点。该数据揭示了泛素样蛋白如何通过变构间接诱导蛋白质-蛋白质相互作用。泛素样蛋白修饰的变构特异性可能为治疗靶向提供机会。

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