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Genetics. 2018 Jan;208(1):419-431. doi: 10.1534/genetics.117.300377. Epub 2017 Nov 10.

Protein Moonlighting Revealed by Noncatalytic Phenotypes of Yeast Enzymes.

Author information

1
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad de Genómica Avanzada (Langebio), 36821 Irapuato, Guanajuato, Mexico.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158.
3
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad de Genómica Avanzada (Langebio), 36821 Irapuato, Guanajuato, Mexico alexander.deluna@cinvestav.mx.

Abstract

A single gene can partake in several biological processes, and therefore gene deletions can lead to different-sometimes unexpected-phenotypes. However, it is not always clear whether such pleiotropy reflects the loss of a unique molecular activity involved in different processes or the loss of a multifunctional protein. Here, using Saccharomyces cerevisiae metabolism as a model, we systematically test the null hypothesis that enzyme phenotypes depend on a single annotated molecular function, namely their catalysis. We screened a set of carefully selected genes by quantifying the contribution of catalysis to gene deletion phenotypes under different environmental conditions. While most phenotypes were explained by loss of catalysis, slow growth was readily rescued by a catalytically inactive protein in about one-third of the enzymes tested. Such noncatalytic phenotypes were frequent in the Alt1 and Bat2 transaminases and in the isoleucine/valine biosynthetic enzymes Ilv1 and Ilv2, suggesting novel "moonlighting" activities in these proteins. Furthermore, differential genetic interaction profiles of gene deletion and catalytic mutants indicated that ILV1 is functionally associated with regulatory processes, specifically to chromatin modification. Our systematic study shows that gene loss phenotypes and their genetic interactions are frequently not driven by the loss of an annotated catalytic function, underscoring the moonlighting nature of cellular metabolism.

KEYWORDS:

Saccharomyces cerevisiae; amino acid biosynthesis; metabolism; phenotype; pleiotropy; protein moonlighting; systems genetics

PMID:
29127264
PMCID:
PMC5753873
DOI:
10.1534/genetics.117.300377
[Indexed for MEDLINE]
Free PMC Article

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