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Structural and functional asymmetry of RING trimerization controls priming and extension events in TRIM5α autoubiquitylation
Nature Communications ( IF 14.7 ) Pub Date : 2022-11-19 , DOI: 10.1038/s41467-022-34920-3
Frank Herkules 1 , Corey H Yu 1 , Alexander B Taylor 1 , Vi Dougherty 1 , Susan T Weintraub 1 , Dmitri N Ivanov 1
Affiliation  

TRIM5α is an E3 ubiquitin ligase of the TRIM family that binds to the capsids of primate immunodeficiency viruses and blocks viral replication after cell entry. Here we investigate how synthesis of K63-linked polyubiquitin is upregulated by transient proximity of three RING domains in honeycomb-like assemblies formed by TRIM5α on the surface of the retroviral capsid. Proximity of three RINGs creates an asymmetric arrangement, in which two RINGs form a catalytic dimer that activates E2-ubiquitin conjugates and the disordered N-terminus of the third RING acts as the substrate for N-terminal autoubiquitylation. RING dimerization is required for activation of the E2s that contribute to the antiviral function of TRIM5α, UBE2W and heterodimeric UBE2N/V2, whereas the proximity of the third RING enhances the rate of each of the two distinct steps in the autoubiquitylation process: the initial N-terminal monoubiquitylation (priming) of TRIM5α by UBE2W and the subsequent extension of the K63-linked polyubiquitin chain by UBE2N/V2. The mechanism we describe explains how recognition of infection-associated epitope patterns by TRIM proteins initiates polyubiquitin-mediated downstream events in innate immunity.



中文翻译:

RING 三聚化的结构和功能不对称性控制 TRIM5α 自泛素化中的启动和延伸事件

TRIM5α 是 TRIM 家族的一种 E3 泛素连接酶,可与灵长类免疫缺陷病毒的衣壳结合,并在进入细胞后阻止病毒复制。在这里,我们研究了 K63 连接的多聚泛素的合成如何通过 TRIM5α 在逆转录病毒衣壳表面形成的蜂窝状组件中的三个 RING 结构域的瞬时接近而上调。三个 RING 的接近产生不对称排列,其中两个 RING 形成催化二聚体,激活 E2-泛素缀合物,第三个 RING 的无序 N 末端充当 N 末端自泛素化的底物。激活有助于 TRIM5α、UBE2W 和异二聚体 UBE2N/V2 的抗病毒功能的 E2 需要 RING 二聚化,而第三个 RING 的接近提高了自身泛素化过程中两个不同步骤中每一个的速率:UBE2W 对 TRIM5α 的初始 N 端单泛素化(启动)和随后由 UBE2N/V2 延伸的 K63 连接的多聚泛素链. 我们描述的机制解释了 TRIM 蛋白对感染相关表位模式的识别如何在先天免疫中启动多聚泛素介导的下游事件。

更新日期:2022-11-19
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