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靶向诱导聚集激活了病原体和蛋白质的 Trim-Away。

Target-induced clustering activates Trim-Away of pathogens and proteins.

机构信息

Medical Research Council, Laboratory of Molecular Biology, Cambridge, UK.

i3S-Instituto de Investigação e Inovação em Saúde and IBMC Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.

出版信息

Nat Struct Mol Biol. 2021 Mar;28(3):278-289. doi: 10.1038/s41594-021-00560-2. Epub 2021 Feb 25.

DOI:10.1038/s41594-021-00560-2
PMID:33633400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7611929/
Abstract

Trim-Away is a recently developed technology that exploits off-the-shelf antibodies and the RING E3 ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically activated upon target engagement, either during its normal immune function or when repurposed for targeted protein degradation, is unknown. Here we show that a mechanism of target-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce virus neutralization or drive Trim-Away. We harness this mechanism for selective degradation of disease-causing huntingtin protein containing long polyglutamine tracts and expand the Trim-Away toolbox with highly active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has implications for targeted protein degradation technologies.

摘要

Trim-Away 是一种最近开发的技术，它利用现成的抗体和 RING E3 连接酶和细胞质抗体受体 TRIM21 来快速进行蛋白质消耗。TRIM21 在靶标结合时如何被催化激活，无论是在其正常免疫功能期间还是在重新用于靶向蛋白降解时，目前尚不清楚。在这里，我们表明，一种靶标诱导聚集的机制触发 RING 结构域的分子间二聚化，从而开启 TRIM21 的泛素化活性，并诱导病毒中和或驱动 Trim-Away。我们利用这种机制来选择性降解含有长多聚谷氨酰胺链的致病 huntingtin 蛋白，并使用高度活跃的 TRIM21-纳米抗体嵌合体扩展 Trim-Away 工具包，该嵌合体也可以光遗传学控制。这项工作为 TRIM RING 连接酶的细胞激活提供了一种机制，并对靶向蛋白降解技术具有重要意义。

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