Cullin-RING ubiquitin ligases (CRLs) are dynamic modular platforms that regulate myriad biological processes through target-specific ubiquitylation. Our knowledge of this system emerged from the F-box hypothesis, posited a quarter century ago: Numerous interchangeable F-box proteins confer specific substrate recognition for a core CUL1-based RING E3 ubiquitin ligase. This paradigm has been expanded through the evolution of a superfamily of analogous modular CRLs, with five major families and over 200 different substrate-binding receptors in humans. Regulation is achieved by numerous factors organized in circuits that dynamically control CRL activation and substrate ubiquitylation. CRLs also serve as a vast landscape for developing small molecules that reshape interactions and promote targeted ubiquitylation-dependent turnover of proteins of interest. Here, we review molecular principles underlying CRL function, the role of allosteric and conformational mechanisms in controlling substrate timing and ubiquitylation, and how the dynamics of substrate receptor interchange drives the turnover of selected target proteins to promote cellular decision making. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

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Cullin-ring泛素连接酶调节电路：超出F-box假说四分之一世纪。

Cullin-ring泛素连接酶（CRL）是动态的模块化平台，可通过靶标特异性泛素化来调节多种生物学过程。我们对该系统的了解来自于25年前的F-box假说：许多可互换的F-box蛋白赋予基于CUL1的RING E3泛素连接酶核心的特异性底物识别能力。该范式已通过在人类中具有五个主要家族和200多种不同的底物结合受体的类似模块化CRL的超家族进化而得以扩展。通过动态控制CRL激活和底物泛素化的电路中组织的众多因素来实现调节。CRL也可作为开发小分子的广阔前景，这些小分子可重塑相互作用并促进目标蛋白的靶向泛素化依赖性周转。在这里，我们回顾了CRL功能的分子原理，变构和构象机制在控制底物时间和泛素化中的作用，以及底物受体交换的动力学如何驱动选定目标蛋白的更新来促进细胞决策。《生物化学年度评论》第90卷的最终最终在线发布日期为2021年6月。请参阅http://www.annualreviews.org/page/journal/pubdates以获取修订的估算值。以及底物受体交换的动力学如何驱动所选靶蛋白的更新来促进细胞决策。《生物化学年度评论》第90卷的最终最终在线发布日期为2021年6月。请参阅http://www.annualreviews.org/page/journal/pubdates以获取修订的估算值。以及底物受体交换的动力学如何驱动所选靶蛋白的更新来促进细胞决策。《生物化学年度评论》第90卷的最终最终在线发布日期为2021年6月。请参阅http://www.annualreviews.org/page/journal/pubdates以获取修订的估算值。