Lorenz Sonja
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
Biol Chem. 2018 Jan 26;399(2):127-145. doi: 10.1515/hsz-2017-0184.
Ubiquitin ligases (E3 enzymes) transfer ubiquitin from ubiquitin-conjugating (E2) enzymes to target proteins. By determining the selection of target proteins, modification sites on those target proteins, and the types of ubiquitin modifications that are formed, E3 enzymes are key specificity factors in ubiquitin signaling. Here, I summarize our knowledge of the structural mechanisms in the HECT E3 subfamily, many members of which play important roles in human disease. I discuss interactions of the conserved HECT domain with E2 enzymes, ubiquitin and target proteins, as well as macromolecular interactions with regulatory functions. While we understand individual steps in the catalytic cycle of HECT E3 enzymes on a structural level, this review also highlights key aspects that have yet to be elucidated. For instance, it remains unclear how diverse target proteins are presented to the catalytic center and how certain HECT E3 enzymes achieve specificity in ubiquitin linkage formation. The structural and functional properties of the N-terminal regions of HECT E3 enzymes that likely act as signaling hubs are also largely unknown. Structural insights into these aspects may open up routes for a therapeutic intervention with specific HECT E3 functions in distinct pathophysiological settings.
泛素连接酶（E3 酶）将泛素从泛素结合（E2）酶转移至靶蛋白。通过决定靶蛋白的选择、这些靶蛋白上的修饰位点以及所形成的泛素修饰类型，E3 酶是泛素信号传导中的关键特异性因子。在此，我总结了我们对 HECT E3 亚家族结构机制的认识，该亚家族的许多成员在人类疾病中发挥重要作用。我讨论了保守的 HECT 结构域与 E2 酶、泛素和靶蛋白的相互作用，以及具有调节功能的大分子相互作用。虽然我们在结构层面上理解了 HECT E3 酶催化循环中的各个步骤，但本综述也强调了尚未阐明的关键方面。例如，尚不清楚多种靶蛋白是如何呈递给催化中心的，以及某些 HECT E3 酶如何在泛素连接形成中实现特异性。可能作为信号枢纽的 HECT E3 酶 N 端区域的结构和功能特性在很大程度上也未知。对这些方面的结构见解可能为在不同病理生理环境中针对特定 HECT E3 功能进行治疗干预开辟途径。
