The AAA+ ATPase p97, a cellular multitool.
The AAA+ ATPase p97, a cellular multitool.
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DOI：
10.1042/bcj20160783
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发表时间：
2017-08-17
期刊：
影响因子：
--
通讯作者：
Freemont PS
中科院分区：
文献类型：
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作者：
Stach L;Freemont PS
Aaa+(与多种细胞活动相关的ATPase)ATPase p97在一系列细胞功能中是必不可少的，包括内质网相关的降解、膜融合、核因子-κB(核因子-kappa-轻链-激活B细胞)的激活和染色质相关的过程，这些过程受泛素化的调节。P97作用于泛素信号事件的下游，利用三磷酸腺苷水解产生的能量从细胞结构或多蛋白复合体中提取底物蛋白。许多p97辅因子已经进化，它们是p97功能所必需的。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，其与p97的络合物使酶能够与广泛的泛素化底物相互作用。P97的一组突变已被证明导致与Paget病和额颞部痴呆相关的多系统蛋白病、包涵体肌病。此外，p97抑制已被认为是在肿瘤中激发蛋白毒性应激的一种很有前途的方法。在这篇综述中，我们将描述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的酶学以及开发用于癌症治疗的p97抑制剂的现状。
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.