1. Linkage-specific ubiquitin chain formation depends on a lysine hydrocarbon ruler.
- Author
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Liwocha J, Krist DT, van der Heden van Noort GJ, Hansen FM, Truong VH, Karayel O, Purser N, Houston D, Burton N, Bostock MJ, Sattler M, Mann M, Harrison JS, Kleiger G, Ovaa H, and Schulman BA
- Subjects
- Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Humans, Kinetics, Lysine metabolism, Models, Molecular, NEDD8 Protein genetics, NEDD8 Protein metabolism, Nuclear Proteins chemistry, Nuclear Proteins genetics, Nuclear Proteins metabolism, Polyubiquitin genetics, Polyubiquitin metabolism, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Secondary, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Substrate Specificity, Transcription Factors chemistry, Transcription Factors genetics, Transcription Factors metabolism, Ubiquitin genetics, Ubiquitin metabolism, Ubiquitin-Conjugating Enzymes chemistry, Ubiquitin-Conjugating Enzymes genetics, Ubiquitin-Conjugating Enzymes metabolism, Ubiquitination, Lysine chemistry, NEDD8 Protein chemistry, Polyubiquitin chemistry, Protein Processing, Post-Translational, Ubiquitin chemistry
- Abstract
Virtually all aspects of cell biology are regulated by a ubiquitin code where distinct ubiquitin chain architectures guide the binding events and itineraries of modified substrates. Various combinations of E2 and E3 enzymes accomplish chain formation by forging isopeptide bonds between the C terminus of their transiently linked donor ubiquitin and a specific nucleophilic amino acid on the acceptor ubiquitin, yet it is unknown whether the fundamental feature of most acceptors-the lysine side chain-affects catalysis. Here, use of synthetic ubiquitins with non-natural acceptor site replacements reveals that the aliphatic side chain specifying reactive amine geometry is a determinant of the ubiquitin code, through unanticipated and complex reliance of many distinct ubiquitin-carrying enzymes on a canonical acceptor lysine.
- Published
- 2021
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