Latent effects of Hsp90 mutants revealed at reduced expression levels
Student Authors
Ryan T. HietpasUMass Chan Affiliations
Program in Bioinformatics and Integrative BiologyDepartment of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2013-06-27Keywords
Amino Acid Sequence; Amino Acid Substitution; Gene Expression Regulation, Fungal; Genetic Fitness; HSP90 Heat-Shock Proteins; Mutation; Point Mutation; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Selection, Genetic; Substrate SpecificityBiochemistry
Molecular Biology
Molecular Genetics
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1371/journal.pgen.1003600Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33307PubMed ID
23825969Related Resources
Link to article in PubMedRights
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.
ae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1003600