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Molecular and Cellular Biology, June 2000, p. 3918-3927, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Role of Saccharomyces cerevisiae ISA1 and ISA2 in Iron Homeostasis

Laran T. Jensen and Valeria Cizewski Culotta*

Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Baltimore, Maryland 21205

Received 3 December 1999/Returned for modification 12 January 2000/Accepted 1 March 2000

The budding yeast Saccharomyces cerevisiae contains two homologues of bacterial IscA proteins, designated Isa1p and Isa2p. Bacterial IscA is a product of the isc (iron-sulfur cluster) operon and has been suggested to participate in Fe-S cluster formation or repair. To test the function of yeast Isa1p and Isa2p, single or combinatorial disruptions were introduced in ISA1 and ISA2. The resultant isaDelta mutants were viable but exhibited a dependency on lysine and glutamate for growth and a respiratory deficiency due to an accumulation of mutations in mitochondrial DNA. As with other yeast genes proposed to function in Fe-S cluster assembly, mitochondrial iron concentration was significantly elevated in the isa mutants, and the activities of the Fe-S cluster-containing enzymes aconitase and succinate dehydrogenase were dramatically reduced. An inspection of Isa-like proteins from bacteria to mammals revealed three invariant cysteine residues, which in the case of Isa1p and Isa2p are essential for function and may be involved in iron binding. As predicted, Isa1p is targeted to the mitochondrial matrix. However, Isa2p is present within the intermembrane space of the mitochondria. Our deletion analyses revealed that Isa2p harbors a bipartite N-terminal leader sequence containing a mitochondrial import signal linked to a second sequence that targets Isa2p to the intermembrane space. Both signals are needed for Isa2p function. A model for the nonredundant roles of Isa1p and Isa2p in delivering iron to sites of the Fe-S cluster assembly is discussed.

* Corresponding author. Mailing address: Johns Hopkins University School of Public Health, 615 N. Wolfe St., Room 7032, Baltimore, MD 21205. Phone: (410) 955-3029. Fax: (410) 955-0116. E-mail: vculotta{at}jhpsh.edu.

Molecular and Cellular Biology, June 2000, p. 3918-3927, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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