Role of Saccharomyces cerevisiae ISA1 and ISA2 in Iron Homeostasis

doi:10.1128/MCB.20.11.3918-3927.2000

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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) operonand has been suggested to participate in Fe-S cluster formationor repair. To test the function of yeast Isa1p and Isa2p, singleor combinatorial disruptions were introduced in ISA1 and ISA2.The resultant isa $Delta$ mutants were viable but exhibited a dependencyon lysine and glutamate for growth and a respiratory deficiencydue to an accumulation of mutations in mitochondrial DNA. As withother yeast genes proposed to function in Fe-S cluster assembly,mitochondrial iron concentration was significantly elevated inthe isa mutants, and the activities of the Fe-S cluster-containingenzymes aconitase and succinate dehydrogenase were dramaticallyreduced. An inspection of Isa-like proteins from bacteria to mammalsrevealed three invariant cysteine residues, which in the caseof Isa1p and Isa2p are essential for function and may be involvedin iron binding. As predicted, Isa1p is targeted to the mitochondrialmatrix. However, Isa2p is present within the intermembrane spaceof the mitochondria. Our deletion analyses revealed that Isa2pharbors a bipartite N-terminal leader sequence containing a mitochondrialimport signal linked to a second sequence that targets Isa2p tothe intermembrane space. Both signals are needed for Isa2p function.A model for the nonredundant roles of Isa1p and Isa2p in deliveringiron to sites of the Fe-S cluster assembly isdiscussed.

^* 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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