Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex.
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⁻¹s⁻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 Fe(2+) 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.
Tsai
Chi-Lin
CL
Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
Barondeau
David P
DP
D000494:Allosteric Regulation; D001692:Biological Transport; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes / Q000502:physiology; D013455:Sulfur / Q000378:metabolism; D000096923:Frataxin
D013437:Carbon-Sulfur Lyases; D007501:Iron; D033862:Iron-Binding Proteins; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D013455:Sulfur; D000096923:Frataxin; C544445:LYRM4 protein, human; C513492:NFS1 protein, human; C080546:cysteine desulfurase