8D4X

Structure of the human UBR5 HECT-type E3 ubiquitin ligase in a dimeric form

Summary for 8D4X

• Entry DOI: 10.2210/pdb8d4x/pdb
• EMDB information: 27201
• Descriptor: E3 ubiquitin-protein ligase UBR5, ZINC ION (2 entities in total)
• Functional Keywords: hect, e3 ligase, dimer, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 621601.70

Authors

Wang, F.,He, Q.,Lin, G.,Li, H. (deposition date: 2022-06-02, release date: 2023-04-19, Last modification date: 2024-06-12)

Primary citation

Wang, F.,He, Q.,Zhan, W.,Yu, Z.,Finkin-Groner, E.,Ma, X.,Lin, G.,Li, H.
Structure of the human UBR5 E3 ubiquitin ligase.
Structure, 31:541-552.e4, 2023

PubMed Abstract: 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.

PubMed: 37040767
DOI: 10.1016/j.str.2023.03.010

Experimental method

ELECTRON MICROSCOPY (2.8 Å)