Structure of the human UBR5 E3 ubiquitin ligase
Open accessPublished version of a preprint
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.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly
Horn-Ghetko, D., Krist, D. T., Prabu, J. R., Baek, K., Mulder, M. P. C., Klügel, M., Scott, D. C., Ovaa, H., Kleiger, G., & Schulman, B. A. (2021) · Nature · doi:10.1038/s41586-021-03197-9 · Cited by 187 · see citing works
Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3
Kamadurai, H. B., Qiu, Y., Deng, A., Harrison, J. S., MacDonald, C., Actis, M., Rodrigues, P., Miller, D. J., Souphron, J., Lewis, S. M., et al. (2013) · eLife · doi:10.7554/elife.00828 · Cited by 165 · see citing works
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- Authors
- Wang, F., He, Q., Zhan, W., Yu, Z., Finkin-Groner, E., Ma, X., Lin, G., & Li, H.
- Affiliations
- Van Andel Institute (US)
- Weill Cornell Medicine (US)
- Tri-Institutional Therapeutics Discovery Institute (US)
- Corresponding author
- Lin, Gang
- Li, Huilin
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 31
- Issue
- 5
- Pages
- 541-552.e4
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC10403316
- OpenAlex
- W4363674181
- Cited by
- 39
- References
- 3
- Citations by year
- 2026: 12 · 2025: 6 · 2024: 13 · 2023: 8
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense (W81XWH2110261)
- National Institutes of Health
- National Cancer Institute (R01CA273716, R01CA231466)
- National Institute of General Medical Sciences (R35GM131754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- UBR5, E3 ubiquitin ligase, HECT domain, protein oligomerization, tetramer, dimers, cancer, metastasis, structure-based drug design
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Mammals, Catalytic Domain, Cryoelectron Microscopy, Ubiquitin, Ubiquitin-Protein Ligases
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