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Molecular and Cellular Biology, September 2008, p. 5569-5582, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00642-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dre2, a Conserved Eukaryotic Fe/S Cluster Protein, Functions in Cytosolic Fe/S Protein Biogenesis

Yan Zhang,¹ Elise R. Lyver,¹ Eiko Nakamaru-Ogiso,² Heeyong Yoon,¹ Boominathan Amutha,³ Dong-Woo Lee,⁴ Erfei Bi,⁵ Tomoko Ohnishi,² Fevzi Daldal,⁴ Debkumar Pain,³ and Andrew Dancis^1*

Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,¹ Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,² Department of Pharmacology and Physiology, The University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07101,³ Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104,⁴ Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104⁵

Received 20 April 2008/ Returned for modification 23 May 2008/ Accepted 2 July 2008

In a forward genetic screen for interaction with mitochondrial iron carrier proteins in Saccharomyces cerevisiae, a hypomorphic mutation of the essential DRE2 gene was found to confer lethality when combined with mrs3 and mrs4. The dre2 mutant or Dre2-depleted cells were deficient in cytosolic Fe/S cluster protein activities while maintaining mitochondrial Fe/S clusters. The Dre2 amino acid sequence was evolutionarily conserved, and cysteine motifs (CX₂CXC and twin CX₂C) in human and yeast proteins were perfectly aligned. The human Dre2 homolog (implicated in blocking apoptosis and called CIAPIN1 or anamorsin) was able to complement the nonviability of a dre2 deletion strain. The Dre2 protein with triple hemagglutinin tag was located in the cytoplasm and in the mitochondrial intermembrane space. Yeast Dre2 overexpressed and purified from bacteria was brown and exhibited signature absorption and electron paramagnetic resonance spectra, indicating the presence of both [2Fe-2S] and [4Fe-4S] clusters. Thus, Dre2 is an essential conserved Fe/S cluster protein implicated in extramitochondrial Fe/S cluster assembly, similar to other components of the so-called CIA (cytoplasmic Fe/S cluster assembly) pathway although partially localized to the mitochondrial intermembrane space.

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* Corresponding author. Mailing address: Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104. Phone: (215) 573-6275. Fax: (215) 573-7049. E-mail: adancis{at}mail.med.upenn.edu

Published ahead of print on 14 July 2008.

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Molecular and Cellular Biology, September 2008, p. 5569-5582, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00642-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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