人类UBR5是一种单肽链，与E6AP C端（HECT型）E3泛素连接酶同源，在哺乳动物的胚胎发育中不可或缺。失调的UBR5功能像一个致癌蛋白质一样促进癌细胞的生长和转移。我们报告UBR5组装成二聚体和四聚体。我们的冷冻电镜（cryo-EM）结构展示了两个新月形UBR5单体头尾相接组成二聚体，两个二聚体面对面结合形成笼状四聚体，其中所有四个催化HECT域朝向中央腔。重要的是，一个亚基的N端区域和另一个的HECT形成了一个“互分子颚骨”在二聚体中。我们证明颚骨内的残基对功能很重要，表明颚骨功能是为了招募负载泛素的E2到UBR5。进一步的工作需要理解寡聚化如何调节UBR5连接酶活性。这项研究提供了一个基于结构的抗癌药物开发框架，并对E3连接酶多样性的不断重视做出了贡献。版权所有 © 2023 Elsevier Ltd.。保留所有权利。

The human UBR5 is a single polypeptide chain homology to E6AP C terminus (HECT)-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis. Here, we report that UBR5 assembles into a dimer and a tetramer. Our cryoelectron microscopy (cryo-EM) structures reveal that two crescent-shaped UBR5 monomers assemble head to tail to form the dimer, and two dimers bind face to face to form the cage-like tetramer with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an "intermolecular jaw" in the dimer. We show the jaw-lining residues are important for function, suggesting that the intermolecular jaw functions to recruit ubiquitin-loaded E2 to UBR5. Further work is needed to understand how oligomerization regulates UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development and contributes to a growing appreciation of E3 ligase diversity.Copyright © 2023 Elsevier Ltd. All rights reserved.