Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants.
Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants.
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DOI：
10.1016/j.abb.2016.08.005
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发表时间：
2017-03-01
影响因子：
3.9
通讯作者：
Canning P
中科院分区：
文献类型：
--
作者：
Dinkova-Kostova AT;Kostov RV;Canning P
Kelch样ECH相关蛋白1(Keap1)是基于cullin3的Cullin环E3泛素连接酶(CRL)多亚单位蛋白复合体的一个组成部分。在CRL中，同源二聚体Keap1作为Cullin3接头发挥作用，重要的是，它也是执行底物识别的E3连接酶的关键成分。Keap1最具特性的底物是转录因子NF-E2 P45相关因子2(NRF2)，它编排了一个复杂的转录程序，以应对氧化剂、亲电体和促炎剂引起的环境挑战，允许在应激条件下适应和生存。Keap1配备了反应性半胱氨酸残基，作为内源产生和外源遇到的小分子(称为诱导剂)的传感器，这些小分子具有特征的化学特征，即与巯基的反应性。诱导剂修饰Keap1的半胱氨酸传感器，削弱其针对Nrf2泛素化和降解的能力。因此，Nrf2积聚，进入细胞核，并驱动其目标基因的转录，这些基因编码一个庞大的细胞保护蛋白网络。在这里，我们总结了导致预测Keap1存在的早期研究，随后发现Keap1是Nrf2的主要负调控因子。然后我们描述了Keap1的可用结构信息，它与Cullin3的组装，以及它与Nrf2的相互作用。我们还讨论了Keap1的多个半胱氨酸传感器，这些传感器允许检测广泛的内源和环境诱导因素，并提供对Keap1/Nrf2压力敏感反应的微调和严格控制。
The Kelch-like ECH associated protein 1 (Keap1) is a component of a Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) multisubunit protein complex. Within the CRL, homodimeric Keap1 functions as the Cullin3 adaptor, and importantly, it is also the critical component of the E3 ligase that performs the substrate recognition. The best-characterized substrate of Keap1 is transcription factor NF-E2 p45-related factor 2 (Nrf2), which orchestrates an elaborate transcriptional program in response to environmental challenges caused by oxidants, electrophiles and pro-inflammatory agents, allowing adaptation and survival under stress conditions. Keap1 is equipped with reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules (termed inducers), which have a characteristic chemical signature, reactivity with sulfhydryl groups. Inducers modify the cysteine sensors of Keap1 and impair its ability to target Nrf2 for ubiquitination and degradation. Consequently, Nrf2 accumulates, enters the nucleus and drives the transcription of its target genes, which encode a large network of cytoprotective proteins. Here we summarize the early studies leading to the prediction of the existence of Keap1, followed by the discovery of Keap1 as the main negative regulator of Nrf2. We then describe the available structural information on Keap1, its assembly with Cullin3, and its interaction with Nrf2. We also discuss the multiple cysteine sensors of Keap1 that allow for detection of a wide range of endogenous and environmental inducers, and provide fine-tuning and tight control of the Keap1/Nrf2 stress-sensing response.