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J. Biol. Chem., Vol. 281, Issue 24, 16551-16562, June 16, 2006

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One Single In-frame AUG Codon Is Responsible for a Diversity of Subcellular Localizations of Glutaredoxin 2 in Saccharomyces cerevisiae^*

Pablo Porras, C. Alicia Padilla, Martin Krayl^¶, Wolfgang Voos, and J. Antonio Bárcena¹

From the Department of Biochemistry and Molecular Biology, University of Córdoba, 14071 Córdoba, Spain and the Institut fuer Biochemie und Molekularbiologie and ^¶Fakultaet fuer Biologie, Universitaet Freiburg, D-79104 Freiburg, Germany

Glutaredoxins belong to a family of small proteins with glutathione-dependent disulfide oxidoreductase activity involved in cellular defense against oxidative stress. The product of the yeast GRX2 gene is a protein that is localized both in the cytosol and mitochondria. To throw light onto the mechanism responsible for the dual subcellular distribution of Grx2 we analyzed mutant constructs containing different targeting information. By altering amino acid residues around the two in-frame translation initiation start sites of the GRX2 gene, we could demonstrate that the cytosolic isoform of Grx2 was synthesized from the second AUG, lacking an N-terminal extension. Translation from the first AUG resulted in a long isoform carrying a mitochondrial targeting presequence. The mitochondrial targeting properties of the presequence and the influence of the mature part of Grx2 were analyzed by the characterization of the import kinetics of specific fusion proteins. Import of the mitochondrial isoform is relatively inefficient and results in the accumulation of a substantial amount of unprocessed form in the mitochondrial outer membrane. Substitution of Met³⁵, the second translation start site, to Val resulted in an exclusive targeting to the mitochondrial matrix. Our results show that a plethora of Grx2 subcellular localizations could spread its antioxidant functions all over the cell, but one single Ala to Gly mutation converts Grx2 into a typical protein of the mitochondrial matrix.

Received for publication, January 26, 2006 , and in revised form, March 30, 2006.

^* The work in Córdoba was supported by the Spanish Ministry of Education (Grant BFI2002-00755) and by annual grants from the Andalusian Government Plan Andaluz de Investigación (PAI) program to the CVI-0216 group. 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 Fig. 1S and Tables 1S, 2S, and 3S (with graph).

¹ To whom correspondence should be addressed: Tel.: 34-957-218-590; Fax: 34-957-218-592; E-mail: bb1barua{at}uco.es.

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