Stach Lasse, Freemont Paul S
Section of Structural Biology, Department of Medicine, Imperial College London, London, U.K.
Biochem J. 2017 Aug 17;474(17):2953-2976. doi: 10.1042/BCJ20160783.
The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.
AAA+（与多种细胞活动相关的ATP酶）ATP酶p97对广泛的细胞功能至关重要，包括内质网相关降解、膜融合、NF-κB（活化B细胞核因子κ轻链增强子）激活以及与染色质相关的过程，这些过程均受泛素化调控。p97在泛素信号事件下游发挥作用，并利用ATP水解产生的能量从细胞结构或多蛋白复合物中提取其底物蛋白。现已进化出多种对p97功能至关重要的p97辅因子。泛素相互作用结构域和p97结合结构域结合形成双功能辅因子，它们与p97的复合物使该酶能够与多种泛素化底物相互作用。已证实p97中的一组突变会导致与骨Paget病和额颞叶痴呆相关的多系统蛋白病包涵体肌病。此外，p97抑制已被确定为在肿瘤中引发蛋白毒性应激的一种有前景的方法。在本综述中，我们将描述由p97调控的细胞过程、辅因子如何与p97及其泛素化底物相互作用、p97酶学以及开发用于癌症治疗的p97抑制剂的现状。
