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Papers In Press, published online ahead of print December 13, 2001
J. Biol. Chem, 10.1074/jbc.M110282200
Submitted on October 25, 2001
Revised on December 13, 2001
Accepted on December 13, 2001

Detection of a [3Fe-4S] cluster intermediate of cytosolic aconitase in yeast expressing iron regulatory protein 1: Insights into the mechanism of Fe-S cluster cycling

Nina M. Brown, M. Claire Kennedy, William E. Antholine, Richard S. Eisenstein, and William E. Walden

Dept. of Microbiology and Immunology (m/c 790), University of Illinois at Chicago, Chicago, IL 60612-7334

Corresponding Author: wwalden{at}uic.edu

Interconversion of iron regulatory protein 1 (IRP1) with cytosolic (c-) aconitase occurs via assembly/disassembly of a [4Fe-4S] cluster. Several lines of evidence implicate oxidants in cluster disassembly. Here we investigated H2O2-initiated Fe-S cluster disassembly in c-aconitase expressed in Saccharomyces cerevisiae. A signal for [3Fe-4S] c-aconitase was detected by whole-cell EPR of aerobically grown, aco1 yeast expressing wild-type IRP1 or a S138A-IRP1 mutant (IRP1S138A), providing the first direct evidence of a 3Fe intermediate in vivo. Exposure of yeast to H2O2 increased this 3Fe c-aconitase signal by as much as 5-fold, coincident with inhibition of c-aconitase activity. Untreated yeast expressing IRP1S138D or IRP1S138E, which mimic phosphorylated IRP1, failed to give a 3Fe signal. Exposure to H2O2 produced a weak 3Fe signal in yeast expressing IRP1S138D. Yeast expressing IRP1S138D or IRP1S138E were also the most sensitive to inhibition of aconitase-dependent growth by H2O2, and were the most responsive to changes in media iron status. Ferricyanide oxidation of anaerobically reconstituted c-aconitase yielded a strong 3Fe EPR signal with wild-type and S138A c-aconitases. In contrast, only a weak 3Fe signal was obtained with S138D c-aconitase, and no signal with S138E c-aconitase. This paired with loss of c-aconitase activity strongly argues that the Fe-S clusters of these phosphomimetic c-aconitase mutants undergo more complete disassembly upon oxidation. Our results demonstrate that 3Fe c-aconitase is an intermediate in H2O2-initiated Fe-S cluster disassembly in vivo, and suggest that cluster assembly/disassembly in IRP1 is a dynamic process in aerobically growing yeast. Our results also lend further support to the view that phosphorylation of IRP1 can modulate its response to iron through effects on Fe-S cluster stability and turnover.


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