Catalysis of Lysine 48-Specific Ubiquitin Chain Assembly by Residues in E2 and Ubiquitin
Open accessAbstract
Protein ubiquitination is catalyzed by ubiquitin-conjugating enzymes (E2s) in collaboration with ubiquitin-protein ligases (E3s). This process depends on nucleophilic attack by a substrate lysine on a thioester bond linking the C terminus of ubiquitin to a cysteine in the E2 active site. Different E2 family members display specificity for lysines in distinct contexts. We addressed the mechanistic basis for this lysine selectivity in Ubc1, an E2 that catalyzes the ubiquitination of lysine 48 (K48) in ubiquitin, leading to the formation of K48-linked polyubiquitin chains. We identified a cluster of polar residues near the Ubc1 active site, as well as a residue in ubiquitin itself, that are required for catalysis of K48-specific ubiquitin ligation, but not for general activity toward other lysines. Our results suggest that the active site of Ubc1, as well as the surface of ubiquitin, contains specificity determinants that channel specific lysines to the central residues involved directly in catalysis.
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Most E2 ligases have a preference for forming specific polyubiquitin chain linkages.
“as most E2 ligases have a preference for forming specific polyubiquitin chain linkages (24,25).”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [25]
The Introduction and Discussion describe E2 enzymes that favor particular ubiquitin linkages, including Ubc1 and Cdc34 for K48 and Ubc13 for K63. They do not establish that most E2 enzymes have such a preference; the Discussion also identifies Ubc4 as a general E2. The paper distinguishes E2 conjugating enzymes from E3 ligases. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDifferential E2 ligase recruitment to IDOL determines the outcome of the ubiquitination reaction.
“However, we find it more plausible that differential E2 ligase recruitment to IDOL determines the outcome of the ubiquitination reaction as most E2 ligases have a preference for forming specific polyubiquitin chain linkages (24,25).”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [25]
The Introduction and Discussion describe linkage preferences for several E2s, including Ubc1 and Cdc34 for K48 and Ubc13 for K63. They do not establish that *most* E2s have such preferences; the Discussion also describes general E2s. The IDOL recruitment proposal is framed as the citing authors’ own explanation, not a finding attributed to this source. (LLM, conf=0.82)
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Research works printed but not linked: 28
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- Authors
- Rodrigo-Brenni, M. C., Foster, S. A., & Morgan, D. O.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Morgan, David O.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 39
- Issue
- 4
- Pages
- 548-559
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2929935
- OpenAlex
- W2112074525
- Cited by
- 91
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 8 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 8
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (GM-53270, R01GM053270, R37GM053270)
- 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
- Ubc1, E2 ubiquitin-conjugating enzyme, ubiquitin chain assembly, active site residues, substrate specificity
- MeSH terms
- Alanine, Binding Sites, Catalysis, Glutamine, Hydrogen-Ion Concentration, Kinetics, Leucine, Lysine, Models, Molecular, Protein Conformation, Protein Processing, Post-Translational, Structure-Activity Relationship, Threonine, Tyrosine, Catalytic Domain, Ubiquitin, Polyubiquitin, Saccharomyces cerevisiae Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitination
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