Proteasome interaction with ubiquitinated substrates: from mechanisms to therapies.
Proteasome interaction with ubiquitinated substrates: from mechanisms to therapies.
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蛋白酶体与泛素化底物的相互作用：从机制到治疗。
DOI：
10.1111/febs.15638
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Walters KJ
中科院分区：
文献类型：
--
作者：
Chen X;Htet ZM;López-Alfonzo E;Martin A;Walters KJ
26S蛋白酶体负责真核细胞中调节的蛋白质水解。它的底物在结构、功能、序列长度和氨基酸组成上是多样的，并且通过泛素的翻译后修饰靶向蛋白酶体。泛素化通过复杂的酶级联反应发生，也可以为其他细胞事件发出信号，与蛋白酶体催化的降解无关。与其他翻译后蛋白质修饰一样，泛素化是可逆的，泛素链水解由去泛素化酶（DUB）的作用催化，其中约90种存在于人类中，并允许时间事件以及动态泛素链重塑。几十年来，DUB一直被认为是蛋白酶体的组成部分，因为去泛素化与底物解折叠和易位到内部降解室相耦合。此外，蛋白酶体还结合几种遍在化酶以及招募遍在化底物的穿梭因子。这种复杂的机制的作用以及泛素化底物如何与蛋白酶体相互作用仍然是一个活跃的研究领域。在这里，我们回顾了已经了解到的蛋白酶体结合泛素化底物，底物穿梭因子，泛素化机制，DUBs的机制。我们还讨论了许多需要进一步研究或开发创新方法才能回答的悬而未决的问题。最后，我们讨论了扩大治疗靶向的希望，可以从这些新发现中受益。
The 26S proteasome is responsible for regulated proteolysis in eukaryotic cells. Its substrates are diverse in structure, function, sequence length, and amino acid composition, and are targeted to the proteasome by post-translational modification with ubiquitin. Ubiquitination occurs through a complex enzymatic cascade and can also signal for other cellular events, unrelated to proteasome-catalyzed degradation. Like other post-translational protein modifications, ubiquitination is reversible, with ubiquitin chain hydrolysis catalyzed by the action of deubiquitinating enzymes (DUBs), ~90 of which exist in humans and allow for temporal events as well as dynamic ubiquitin-chain remodeling. DUBs have been known for decades to be an integral part of the proteasome, as deubiquitination is coupled to substrate unfolding and translocation into the internal degradation chamber. Moreover, the proteasome also binds several ubiquitinating enzymes as well as shuttle factors that recruit ubiquitinated substrates. The role of this intricate machinery and how ubiquitinated substrates interact with proteasomes remains an area of active investigation. Here, we review what has been learned about the mechanisms used by the proteasome to bind ubiquitinated substrates, substrate shuttle factors, ubiquitination machinery, and DUBs. We also discuss many open questions that require further study or the development of innovative approaches to be answered. Finally, we address the promise of expanded therapeutic targeting that could benefit from such new discoveries.
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影响因子：
62.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1716305114
发表时间：
2017-12-26
影响因子：
11.1
作者：
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影响因子：
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作者：
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