Capturing a substrate in an activated RING E3/E2–SUMO complex
Open accessAbstract
Post-translational protein modification by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as small ubiquitin-like modifier (SUMO) regulates processes including protein homeostasis, the DNA damage response, and the cell cycle. Proliferating cell nuclear antigen (PCNA) is modified by Ub or poly-Ub at lysine (Lys)164 after DNA damage to recruit repair factors. Yeast PCNA is modified by SUMO on Lys164 and Lys127 during S-phase to recruit the anti-recombinogenic helicase Srs2. Lys164 modification requires specialized E2/E3 enzyme pairs for SUMO or Ub conjugation. For SUMO, Lys164 modification is strictly dependent on the E3 ligase Siz1, suggesting the E3 alters E2 specificity to promote Lys164 modification. The structural basis for substrate interactions in activated E3/E2–Ub/Ubl complexes remains unclear. Here we report an engineered E2 protein and cross-linking strategies that trap an E3/E2–Ubl/substrate complex for structure determination, illustrating how an E3 can bypass E2 specificity to force-feed a substrate lysine into the E2 active site.
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The chemical trap in the neddylated CRL1β-TRCP-UBE2D~UB-IκBα intermediate superimposes with consensus acceptors visualized in active sites of sumoylation and neddylation intermediates.
“The chemical trap superimposes with consensus acceptors visualized in active sites of sumoylation63 and neddylation39 intermediates”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [63]
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References 54 · Cited by 108
- Authors
- Streich Jr, F. C., & Lima, C. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lima, Christopher D.
- ORCID
- Lima, Christopher D.
- Venue
- Nature
- Published
- 2016-08-10
- Volume
- 536
- Issue
- 7616
- Pages
- 304-308
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5019495
- OpenAlex
- W2478205319
- Cited by
- 108
- References
- 54
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 13 · 2023: 13 · 2022: 8 · 2021: 18 · 2020: 13 · 2019: 11 · 2018: 7 · 2017: 8 · 2016: 2
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy
- National Institutes of Health
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (GM118080, R01GM065872, GM065872, P41GM103403, R35GM118080)
- National Center for Research Resources (S10RR029205)
- 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 Structure and Dynamics
- Keywords
- SUMOylation, PCNA, SIZ1, E3 ubiquitin ligase, E2 ubiquitin-conjugating enzyme, protein engineering, crosslinking, DNA damage response, Srs2 helicase, ubiquitin-like proteins
- MeSH terms
- Cross-Linking Reagents, DNA Damage, DNA Helicases, Enzyme Activation, Lysine, Protein Binding, Saccharomyces cerevisiae, Substrate Specificity, Ubiquitins, Protein Engineering, Proliferating Cell Nuclear Antigen, Catalytic Domain, Ubiquitin, Small Ubiquitin-Related Modifier Proteins, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases, Multiprotein Complexes, RING Finger Domains
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