Structure of the human UBR5 E3 ubiquitin ligase

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 pro-mote 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 jawin the dimer. We show the jaw-lining residues are impor-tant 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.

Automated summary

The human UBR5 is a HECT-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions as an oncoprotein to promote cancer growth and metastasis. This study reveals the assembly of UBR5 into a dimer and a tetramer, providing insights into its structure and potential anticancer drug development.