E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages
Abstract
An E3 ubiquitin ligase mediates the transfer of activated ubiquitin from an E2 ubiquitin-conjugating enzyme to its substrate lysine residues. Using a structure-based, yeast two-hybrid strategy, we discovered six previously unidentified interactions between the human heterodimeric RING E3 BRCA1-BARD1 and the human E2s UbcH6, Ube2e2, UbcM2, Ubc13, Ube2k and Ube2w. All six E2s bind directly to the BRCA1 RING motif and are active with BRCA1-BARD1 for autoubiquitination in vitro. Four of the E2s direct monoubiquitination of BRCA1. Ubc13-Mms2 and Ube2k direct the synthesis of Lys63- or Lys48-linked ubiquitin chains on BRCA1 and require an acceptor ubiquitin attached to BRCA1. Differences between the mono- and polyubiquitination activities of the BRCA1-interacting E2s correlate with their ability to bind ubiquitin noncovalently at a site distal to the active site. Thus, BRCA1 has the ability to direct the synthesis of specific polyubiquitin chain linkages, depending on the E2 bound to its RING.
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Specific E2-E3 interactions can control the nature of the ubiquitin linkage that is formed.
“Furthermore, it is now clear that specific E2-E3 interactions can control the nature of the ubiquitin linkage that is formed, as was shown for the BRCA1 RING (28).”
The Brca1-Bard1 complex recruits only a subset of E2 enzymes, and only some of these are capable of transferring ubiquitin to target lysines.
“Moreover, the Brca1–Bard1 complex recruits only a subset of E2 enzymes, and only some of these are actually capable of transferring ubiquitin to target lysines [21].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [21]
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- Authors
- Christensen, D. E., Brzovic, P. S., & Klevit, R. E.
- Affiliations
- University of Washington (US)
- Corresponding author
- Klevit, Rachel E
- Venue
- Nature Structural & Molecular Biology
- Published
- 2007-09-16
- Volume
- 14
- Issue
- 10
- Pages
- 941-948
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2041517382
- Cited by
- 351
- References
- 30
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 10 · 2023: 12 · 2022: 17 · 2021: 16 · 2020: 12 · 2019: 18 · 2018: 18 · 2017: 16 · 2016: 18 · 2015: 19 · 2014: 21 · 2013: 20 · 2012: 23
- FWCI
- 11.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA079953)
- National Institute of General Medical Sciences (T32GM007270)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BRCA1, BARD1, E3 ubiquitin ligase, E2 ubiquitin-conjugating enzyme, RING domain, monoubiquitination, K63-linked ubiquitin, K48-linked ubiquitin, UBE2K, autoubiquitination, ubiquitin transfer
- MeSH terms
- Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Recombinant Fusion Proteins, Sequence Alignment, BRCA1 Protein, Two-Hybrid System Techniques, Protein Structure, Quaternary, Tumor Suppressor Proteins, Polyubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, RING Finger Domains
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