Journal
BIOCHEMISTRY
Volume 49, Issue 43, Pages 9132-9139Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi1013062
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Funding
- Texas AM University
- Robert A. Welch Foundation [A-1647]
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Cellular depletion of the human protein frataxin is correlated with the neurodegenerative disease Friedreich's ataxia and results in the inactivation of Fe-S cluster proteins. Most researchers agree that frataxin functions in the biogenesis of Fe-S clusters, but its precise role in this process is unclear. Here we provide in vitro evidence that human frataxin binds to a Nfs1, Isd11, and Isu2 complex to generate the four-component core machinery for Fe-S cluster biosynthesis. Frataxin binding dramatically changes the K-M for cysteine from 0.59 to 0.011 mM and the catalytic efficiency (K-cat/K-M) of the cysteine desulfurase from 25 to 7900 M-1 S-1 Oxidizing conditions diminish the levels of both complex formation and frataxin-based activation, whereas ferrous iron further stimulates cysteine desulfurase activity. Together, these results indicate human frataxin functions with Fe2+ as an allosteric activator that triggers sulfur delivery and Fe-S cluster assembly. We propose a model in which cellular frataxin levels regulate human Fe-S cluster biosynthesis that has implications for mitochondrial dysfunction, oxidative stress response, and both neurodegenerative and cardiovascular disease.
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