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J. Biol. Chem., Vol. 279, Issue 10, 9462-9474, March 5, 2004

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The Schizosaccharomyces pombe Corepressor Tup11 Interacts with the Iron-responsive Transcription Factor Fep1^*

Sadri Znaidi, Benoit Pelletier¶, Yukio Mukai||, and Simon Labbé**

From the Département de Biochimie, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada and the ^||Department of Biotechnology, Osaka University, Osaka 565-0871, Japan

The Schizosaccharomyces pombe fep1⁺ gene encodes a GATA transcription factor that represses the expression of iron transport genes in response to elevated iron concentrations. This transcriptional response is altered only in strains harboring a combined deletion of both tup11⁺ and tup12⁺ genes. This suggests that Tup11 is capable of negatively regulating iron transport gene expression in the absence of Tup12 and vice versa. The tup11⁺- and tup12⁺-encoded proteins resemble the Saccharomyces cerevisiae Tup1 corepressor. Using yeast two-hybrid analysis we show that Tup11 and Fep1 physically interact with each other. The C-terminal region from amino acids 242 to 564 of Fep1 is required for interaction with Tup11. Within this region, a minimal domain encompassing amino acids 405-541 was sufficient for Tup11-Fep1 association. Deletion mapping analysis revealed that the WD40-repeat sequence motifs of Tup11 are necessary for its interaction with Fep1. Analysis of Tup11 mutants with single amino acid substitutions in the WD40 repeats suggested that the Fep1 transcription factor interacts with a putative flat upper surface on the predicted -propeller structure of this motif. Further analysis by in vivo coimmunoprecipitation showed that Tup11 and Fep1 are physically associated. In vitro pull-down experiments further verified a direct interaction between the Fep1 C terminus and the Tup11 C-terminal WD40 repeat domain. Taken together, these results describe the first example of a physical interaction between a corepressor and an iron-sensing factor controlling the expression of iron uptake genes.

Received for publication, November 24, 2003

Tup11, allows the propeller of Tup11 (B and C, shown in green) to overlay remarkably well with that of Tup1. Predicted regions of Tup11 that differ from Tup1 are shown in red (B and C). Using the DeepView program (59), ribbon representations (B and C) of the three-dimensional structure of Tup11 were obtained. B, view from the top surface of the -propeller. The blades are numbered according to the Tup1 propeller structure. The positions of the mutations that affect the Tup11-Fep1 interaction are indicated with arrows. C, view from the side highlighting the fact that Tyr³⁶² and Leu⁵⁴² residues are exposed and located on the same surface of the -propeller. D, space-filled representation of the C-terminal WD40 domain of Tup11 emphasizing the accessibility of the Tyr³⁶² and Leu⁵⁴² residues (shown in green) for interaction with Fep1.

^* This study was supported by the NSERC of Canada Grant 238238-01 (to S. L.). 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.

Supported in part by the Université de Sherbrooke Faculty of Medicine.

^¶ Recipient of studentships from the NSERC of Canada and Fonds de la Recherche en Santé du Québec.

^** A New Investigator Scholar from the Canadian Institutes of Health Research. To whom correspondence should be addressed: Département de Biochimie, Faculté de Médecine, Université de Sherbrooke, 3001 12e Ave Nord, Sherbrooke (Québec) J1H 5N4 Canada. Tel.: 819-820-6868 (ext. 15460); Fax: 819-564-5340; E-mail: Simon.Labbe{at}USherbrooke.ca.

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