Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases
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Despite the widespread importance of RING/U-box E3 ubiquitin ligases in ubiquitin (Ub) signaling, the mechanism by which this class of enzymes facilitates Ub transfer remains enigmatic. Here, we present a structural model for a RING/U-box E3:E2~Ub complex poised for Ub transfer. The model and additional analyses reveal that E3 binding biases dynamic E2~Ub ensembles toward closed conformations with enhanced reactivity for substrate lysines. We identify a key hydrogen bond between a highly conserved E3 side chain and an E2 backbone carbonyl, observed in all structures of active RING/U-Box E3/E2 pairs, as the linchpin for allosteric activation of E2~Ub. The conformational biasing mechanism is generalizable across diverse E2s and RING/U-box E3s, but is not shared by HECT-type E3s. The results provide a structural model for a RING/U-box E3:E2~Ub ligase complex and identify the long sought-after source of allostery for RING/U-Box activation of E2~Ub conjugates.
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Compared to prior isolated RING-UBE2D~UB structures, the neddylated CRL1β-TRCP-UBE2D~UB-substrate intermediate shows additional density corresponding to the substrate proxy along a trajectory to the ubiquitylation active site.
“Compared to prior isolated RING-UBE2D~UB structures28–30, the neddylated CRL1β-TRCP-UBE2D~UB-substrate intermediate shows additional density corresponding to the substrate proxy along a trajectory to the ubiquitylation active site”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [30]
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- Authors
- Pruneda, J. N., Littlefield, P. J., Soss, S. E., Nordquist, K. A., Chazin, W. J., Brzovic, P. S., & Klevit, R. E.
- Affiliations
- University of Washington (US)
- Vanderbilt University (US)
- Corresponding author
- Klevit, Rachel E.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 47
- Issue
- 6
- Pages
- 933-942
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3462262
- OpenAlex
- W1982004004
- Cited by
- 333
- References
- 36
- Citations by year
- 2026: 24 · 2025: 23 · 2024: 23 · 2023: 18 · 2022: 17 · 2021: 18 · 2020: 28 · 2019: 22 · 2018: 18 · 2017: 23 · 2016: 29 · 2015: 25 · 2014: 33 · 2013: 29 · 2012: 3
- FWCI
- 11.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Energy
- Vanderbilt University
- National Institutes of Health
- U.S. Public Health Service
- National Cancer Institute (P50 CA068485, T32CA009582, P30CA068485)
- National Institute of General Medical Sciences (R01GM088055, R01GM075156, T32GM007270, R01GM098503)
- National Institute of Environmental Health Sciences (P30ES000267, P30 ES0000267)
- National Center for Research Resources (S10RR019133)
- Biological and Environmental Research
- Pacific Northwest National Laboratory
- 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
- allosteric activation, hydrogen bonding, HECT E3 ligases
- MeSH terms
- Hydrogen Bonding, Protein Binding, Protein Conformation, Signal Transduction, Crystallography, X-Ray, Protein Subunits, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases
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