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Molecular and Cellular Biology, June 2000, p. 3918-3927, Vol. 20, No. 11
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 isa
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Role of Saccharomyces cerevisiae ISA1
and ISA2 in Iron Homeostasis
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.
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