Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98195; email:
Annu Rev Biochem. 2017 Jun 20;86:129-157. doi: 10.1146/annurev-biochem-060815-014922. Epub 2017 Mar 27.
Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins. Early investigations of E3s of the RING (really interesting new gene) and HECT (homologous to the E6AP carboxyl terminus) types shed light on their enzymatic activities, general architectures, and substrate degron-binding modes. Recent studies have provided deeper mechanistic insights into their catalysis, activation, and regulation. In this review, we summarize the current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms. Our increased understanding of ubiquitin ligase function and regulation has provided the rationale for developing E3-targeting therapeutics for the treatment of human diseases.
泛素 E3 连接酶通过促进蛋白质泛素化和降解来控制真核生物生物学的各个方面。在三酶级联反应的末端，泛素连接酶介导泛素从 E2 泛素连接酶转移到特定的底物蛋白上。对 RING（真正有趣的新基因）和 HECT（E6AP 羧基末端同源物）类型的 E3 的早期研究揭示了它们的酶活性、一般结构和底物降解基序结合模式。最近的研究为它们的催化、激活和调节提供了更深入的机制见解。在这篇综述中，我们总结了泛素连接酶结构-功能研究的最新进展，以及对新型 E3 类和多种底物识别机制的令人兴奋的新发现。我们对泛素连接酶功能和调节的理解的提高为开发针对人类疾病的 E3 靶向治疗提供了依据。
