ArticleProceedings of the National Academy of Sciences of the United States of America2014
Pivotal role for the ubiquitin Y59-E51 loop in lysine 48 polyubiquitination.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Genetic Code Expansion Approaches to Decipher the Ubiquitin Code.Chemical reviews · 2024Review
- Mechanism of degrader-targeted protein ubiquitinability.Science advances · 2024Article
- Bacterial ligases reveal fundamental principles of polyubiquitin specificity.Molecular cell · 2023Article
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Bacterial mimicry of eukaryotic HECT ubiquitin ligation.bioRxiv : the preprint server for biology · 2023Article
- From seeds to trees: how E2 enzymes grow ubiquitin chains.Biochemical Society transactions · 2023Review
- Ubiquitin-Conjugating Enzymes in Cancer.Cells · 2021Review
- A Novel Strategy to Track Lysine-48 Ubiquitination by Fluorescence Resonance Energy Transfer.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Targeting Phosphotyrosine in Native Proteins with Conditional, Bispecific Antibody Traps.Journal of the American Chemical Society · 2020Article
- Enzymatic Logic of Ubiquitin Chain Assembly.Frontiers in physiology · 2019Review
- Nonenzymatic acetylation of ubiquitin Lys side chains is modulated by their neighboring residues.The FEBS journal · 2018Article
- Site-specific incorporation of phosphotyrosine using an expanded genetic code.Nature chemical biology · 2017Article
- Cullin neddylation may allosterically tune polyubiquitin chain length and topology.The Biochemical journal · 2017Article
- Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3.The Biochemical journal · 2016Review
- Mechanism of Lysine 48 Selectivity during Polyubiquitin Chain Formation by the Ube2R1/2 Ubiquitin-Conjugating Enzyme.Molecular and cellular biology · 2016Article
- Suramin inhibits cullin-RING E3 ubiquitin ligases.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- E2 enzymes: more than just middle men.Cell research · 2016Review
- The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K.Scientific reports · 2015Article
- A new FRET-based platform to track substrate ubiquitination by fluorescence.The Journal of biological chemistryArticle
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18 authors.
Funding
Abstract
Lysine 48 (K48)-polyubiquitination is the predominant mechanism for mediating selective protein degradation, but the underlying molecular basis of selecting ubiquitin (Ub) K48 for linkage-specific chain synthesis remains elusive. Here, we present biochemical, structural, and cell-based evidence demonstrating a pivotal role for the Ub Y59-E51 loop in supporting K48-polyubiquitination. This loop is established by a hydrogen bond between Ub Y59's hydroxyl group and the backbone amide of Ub E51, as substantiated by NMR spectroscopic analysis. Loop residues Y59 and R54 are specifically required for the receptor activity enabling K48 to attack the donor Ub-E2 thiol ester in reconstituted ubiquitination catalyzed by Skp1-Cullin1-F-box (SCF)(βTrCP) E3 ligase and Cdc34 E2-conjugating enzyme. When introduced into mammalian cells, loop-disruptive mutant Ub(R54A/Y59A) diminished the production of K48-polyubiquitin chains. Importantly, conditional replacement of human endogenous Ub by Ub(R54A/Y59A) or Ub(K48R) yielded profound apoptosis at a similar extent, underscoring the global impact of the Ub Y59-E51 loop in cellular K48-polyubiquitination. Finally, disulfide cross-linking revealed interactions between the donor Ub-bound Cdc34 acidic loop and the Ub K48 site, as well as residues within the Y59-E51 loop, suggesting a mechanism in which the Ub Y59-E51 loop helps recruit the E2 acidic loop that aligns the receptor Ub K48 to the donor Ub for catalysis.
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