Department of Biochemistry and Molecular Pharmacology
Biochemistry | Biophysics | Computational Biology | Genomics | Other Ecology and Evolutionary Biology | Systems Biology
Ubiquitin is essential for eukaryotic life and varies in only 3 amino acid positions between yeast and humans. However, recent deep sequencing studies indicate that ubiquitin is highly tolerant to single mutations. We hypothesized that this tolerance would be reduced by chemically induced physiologic perturbations. To test this hypothesis, a class of first year UCSF graduate students employed deep mutational scanning to determine the fitness landscape of all possible single residue mutations in the presence of five different small molecule perturbations. These perturbations uncover 'shared sensitized positions' localized to areas around the hydrophobic patch and the C-terminus. In addition, we identified perturbation specific effects such as a sensitization of His68 in HU and a tolerance to mutation at Lys63 in DTT. Our data show how chemical stresses can reduce buffering effects in the ubiquitin proteasome system. Finally, this study demonstrates the potential of lab-based interdisciplinary graduate curriculum.
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Citation: Elife. 2016 Apr 25;5. pii: e15802. doi: 10.7554/eLife.15802. Link to article on publisher's site
Copyright © 2016, Mavor et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
DOI of Published Version
S. cerevisiae, biophysics, chemical biology, computational biology, deep mutational scanning, evolutionary biology, genomics, proteasome, proteostasis, systems biology, ubiquitin
Mavor, David; Roscoe, Benjamin P.; Bolon, Daniel N.; and Fraser, James S., "Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting" (2016). Open Access Articles. 2854.
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This work is licensed under a Creative Commons Attribution 4.0 License.