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Mechanism and regulation of the Lys6-selective deubiquitinase USP30
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date :  , DOI: 10.1038/nsmb.3475
Malte Gersch , Christina Gladkova , Alexander F Schubert , Martin A Michel , Sarah Maslen , David Komander

Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces. We assess the interplay between USP30, PINK1 and Parkin and show that distally phosphorylated ubiquitin chains impair USP30 activity. Lys6-linkage-specific affimers identify numerous mitochondrial substrates for this modification, and we show that USP30 regulates Lys6-polyubiquitinated TOM20. Our work provides insights into the architecture, activity and regulation of USP30, which will aid drug design against this and related enzymes.

中文翻译:

Lys6选择性去泛素酶USP30的机制和调控

受损的线粒体经历线粒体吞噬,这是一种特殊的自噬​​形式,由蛋白激酶PINK1和泛素E3连接酶Parkin引发。泛素特异性蛋白酶USP30拮抗Parkin介导的线粒体泛素化​​事件,并且是线粒体的关键负调控因子。Parkin和USP30都分别显示了Lys6连接的多聚泛素的组装或拆卸偏好,这种链型尚未得到充分研究。在这里,我们报告人USP30与单泛素和Lys6连接的双泛素结合的晶体结构,这解释了USP30如何通过独特的泛素结合界面实现Lys6连锁偏好。我们评估USP30,PINK1和帕金之间的相互作用,并表明远端磷酸化的泛素链会损害USP30的活性。Lys6连锁特定亲和者确定此修饰的许多线粒体底物,我们表明,USP30调节Lys6多聚泛素化的TOM20。我们的工作提供有关USP30的结构,活性和调控的见解,这将有助于针对该酶和相关酶的药物设计。
更新日期:2017-09-25
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