Journal of Biological Chemistry
Volume 282, Issue 3, 19 January 2007, Pages 1534-1538
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Understanding a Transcriptional Paradigm at the Molecular Level: THE STRUCTURE OF YEAST Gal80p*

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In yeast, the GAL genes encode the enzymes required for normal galactose metabolism. Regulation of these genes in response to the organism being challenged with galactose has served as a paradigm for eukaryotic transcriptional control over the last 50 years. Three proteins, the activator Gal4p, the repressor Gal80p, and the ligand sensor Gal3p, control the switch between inert and active gene expression. Gal80p, the focus of this investigation, plays a pivotal role both in terms of repressing the activity of Gal4p and allowing the GAL switch to respond to galactose. Here we present the three-dimensional structure of Gal80p from Kluyveromyces lactis and show that it is structurally homologous to glucose-fructose oxidoreductase, an enzyme in the sorbitol-gluconate pathway. Our results clearly define the overall tertiary and quaternary structure of Gal80p and suggest that Gal4p and Gal3p bind to Gal80p at distinct but overlapping sites. In addition to providing a molecular basis for previous biochemical and genetic studies, our structure demonstrates that much of the enzymatic scaffold of the oxidoreductase has been maintained in Gal80p, but it is utilized in a very different manner to facilitate transcriptional regulation.

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*

This work was supported by National Institutes of Health Grant DK47814 (to H. M. H.) and by a grant from the Wellcome Trust and Biotechnology and Biological Sciences Research Council (to R. J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Figs. S1 and S2, and Tables S1–S3. The atomic coordinates and structure factors (code 2NVW) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).