4 years ago

Protein Moonlighting Revealed by Non-catalytic Phenotypes of Yeast Enzymes.

Alexander DeLuna, Selene Herrera-Basurto, Adriana Espinosa-Cantú, Diana Ascencio, Jiewei Xu, Nevan J Krogan, Assen Roguev
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 non-catalytic 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 to 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.

Publisher URL: http://doi.org/10.1534/genetics.117.300377

DOI: 10.1534/genetics.117.300377

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