Meyer Hemmo, van den Boom Johannes
Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
Front Mol Biosci. 2023 Feb 7;10:1142989. doi: 10.3389/fmolb.2023.1142989. eCollection 2023.
The AAA+ ATPase p97 (also called VCP or Cdc48) is a major protein unfolding machine with hundreds of clients in diverse cellular pathways that are critical for cell homeostasis, proliferation and signaling. In this review, we summarize recent advances in understanding how diverse client proteins are targeted to the p97 machine to facilitate client degradation or to strip clients from binding partners for regulation. We describe an elaborate system that is governed by at least two types of alternative adapters. The Ufd1-Npl4 adapter along with accessory adapters targets ubiquitylated clients in the majority of pathways and uses ubiquitin as a universal unfolding tag. In contrast, the family of SEP-domain adapters such as p37 can target clients directly to p97 in a ubiquitin-independent manner. Despite the different targeting strategies, both pathways converge by inserting the client into the p97 pore to initiate a peptide threading mechanism through the central channel of p97 that drives client protein unfolding, protein extraction from membranes and protein complex disassembly processes.
AAA+ ATP酶p97（也称为VCP或Cdc48）是一种主要的蛋白质解折叠机器，在多种细胞途径中有数百个作用对象，这些途径对细胞稳态、增殖和信号传导至关重要。在本综述中，我们总结了在理解不同的作用对象蛋白如何被靶向p97机器以促进作用对象降解或从结合伙伴中剥离作用对象以进行调控方面的最新进展。我们描述了一个由至少两种类型的替代衔接子控制的精细系统。Ufd1-Npl4衔接子与辅助衔接子一起在大多数途径中靶向泛素化的作用对象，并将泛素用作通用的解折叠标签。相比之下，SEP结构域衔接子家族，如p37，可以以不依赖泛素的方式将作用对象直接靶向p97。尽管靶向策略不同，但两条途径都通过将作用对象插入p97孔中，启动一种肽穿线机制，穿过p97的中央通道，驱动作用对象蛋白解折叠、从膜上提取蛋白以及蛋白质复合物解体过程。
