HUWE1 is a universal quality-control E3 ligase that marks diverse client proteins for proteasomal degradation. Although the giant HECT enzyme is an essential component of the ubiquitin–proteasome system closely linked with severe human diseases, its molecular mechanism is little understood. Here, we present the crystal structure of Nematocida HUWE1, revealing how a single E3 enzyme has specificity for a multitude of unrelated substrates. The protein adopts a remarkable snake-like structure, where the C-terminal HECT domain heads an extended alpha-solenoid body that coils in on itself and houses various protein–protein interaction modules. Our integrative structural analysis shows that this ring structure is highly dynamic, enabling the flexible HECT domain to reach protein targets presented by the various acceptor sites. Together, our data demonstrate how HUWE1 is regulated by its unique structure, adapting a promiscuous E3 ligase to selectively target unassembled orphan proteins.

HUWE1 是一种通用的质量控制 E3 连接酶，可标记多种客户蛋白以进行蛋白酶体降解。尽管巨型 HECT 酶是与严重人类疾病密切相关的泛素-蛋白酶体系统的重要组成部分，但其分子机制却鲜为人知。在这里，我们展示了杀线虫的晶体结构HUWE1，揭示了一种 E3 酶如何对多种不相关的底物具有特异性。该蛋白质采用了一种显着的蛇状结构，其中 C 端 HECT 结构域指向一个扩展的 α 螺线管体，该螺线管体自行盘绕并容纳各种蛋白质-蛋白质相互作用模块。我们的综合结构分析表明，这种环结构是高度动态的，使灵活的 HECT 结构域能够到达各种受体位点呈现的蛋白质靶标。总之，我们的数据证明了 HUWE1 如何受其独特结构的调节，使混杂的 E3 连接酶选择性地靶向未组装的孤儿蛋白。