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    Latent effects of Hsp90 mutants revealed at reduced expression levels

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    Authors
    Jiang, Li
    Mishra, Parul
    Hietpas, Ryan T.
    Zeldovich, Konstantin B.
    Bolon, Daniel N. A.
    Student Authors
    Ryan T. Hietpas
    UMass Chan Affiliations
    Program in Bioinformatics and Integrative Biology
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2013-06-27
    Keywords
    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 Specificity
    Biochemistry
    Molecular Biology
    Molecular Genetics
    
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    Abstract
    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.1003600
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/33307
    PubMed ID
    23825969
    Related Resources
    Link to article in PubMed
    Rights

    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
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    Morningside Graduate School of Biomedical Sciences Scholarly Publications
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