Apr 26, 2016

Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting

ELife
David MavorJames S Fraser

Abstract

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.

  • References54
  • Citations27

Citations

Mentioned in this Paper

Proteasome Pathway
Ubiquitin
Determination Aspects
Yeasts
Mutant Proteins
Ubiquitin Activity
Lysine
Chemically Induced
Student
Proteasome Complex Location (Sensu Eukarya)

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