Department of Biochemistry and Molecular Pharmacology; Program in Bioinformatics and Integrative Biology
Biochemistry | Molecular Biology | Molecular Genetics
In natural systems, selection acts on both protein sequence and expression level, but it is unclear how selection integrates over these two dimensions. We recently developed the EMPIRIC approach to systematically determine the fitness effects of all possible point mutants for important regions of essential genes in yeast. Here, we systematically investigated the fitness effects of point mutations in a putative substrate binding loop of yeast Hsp90 (Hsp82) over a broad range of expression strengths. Negative epistasis between reduced expression strength and amino acid substitutions was common, and the endogenous expression strength frequently obscured mutant defects. By analyzing fitness effects at varied expression strengths, we were able to uncover all mutant effects on function. The majority of mutants caused partial functional defects, consistent with this region of Hsp90 contributing to a mutation sensitive and critical process. These results demonstrate that important functional regions of proteins can tolerate mutational defects without experimentally observable impacts on fitness.
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Copyright: 2013 Jiang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Jiang L, Mishra P, Hietpas RT, Zeldovich KB, Bolon DNA (2013) Latent Effects of Hsp90 Mutants Revealed at Reduced Expression Levels. PLoS Genet 9(6): e1003600. doi:10.1371/journal.pgen.1003600. Link to article on publisher's site
Jiang L, Mishra P, Hietpas RT, Zeldovich KB, Bolon DN. (2013). Latent effects of Hsp90 mutants revealed at reduced expression levels. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1371/journal.pgen.1003600. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1836