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Abstract
Frataxin, a small mitochondrial protein linked to the neurodegenerative disease Friedreich ataxia, has recently been proposed as an iron donor for the iron-sulfur cluster assembly. An analogous function has also been attributed to IscA, a key member of the iron-sulfur cluster assembly machinery found in bacteria, yeast, and humans. Here we have compared the iron binding property of IscA and the frataxin ortholog CyaY from Escherichia coli under physiological and oxidative stress conditions. In the presence of the thioredoxin reductase system, which emulates the intracellular redox potential, CyaY fails to bind any iron even at a 10-fold excess of iron in the incubation solution. Under the same physiologically relevant conditions, IscA efficiently recruits iron and transfers the iron for the iron-sulfur cluster assembly in a proposed scaffold IscU. In the presence of hydrogen peroxide, however, IscA completely loses its iron binding activity, whereas CyaY becomes a competent iron-binding protein and attenuates the iron-mediated production of hydroxyl free radicals. Hydrogen peroxide appears to oxidize the iron binding thiol groups in IscA, thus blocking the iron binding in the protein. Once the oxidized thiol groups in IscA are re-reduced with the thioredoxin reductase system, the iron binding activity of IscA is fully restored. On the other hand, hydrogen peroxide has no effect on the iron binding carboxyl groups in CyaY, allowing the protein to bind iron under oxidative stress conditions. The results suggest that IscA is capable of recruiting intracellular iron for the iron-sulfur cluster assembly under normal physiological conditions, whereas CyaY may serve as an iron chaperon to sequester redox active free iron and alleviate cellular oxidative damage under oxidative stress conditions.
Highlights
Frataxin is a small mitochondrial protein that has been linked to Friedreich ataxia, an autosomal recessive neurodegenerative disease [1]
Hydrogen peroxide has no effect on the iron binding carboxyl groups in CyaY, allowing the protein to bind iron under oxidative stress conditions
In searching for specific iron donor(s) for biogenesis of ironsulfur clusters, we have discovered that IscA, a key member of the iron-sulfur cluster assembly machinery found in bacteria [35,36,37], yeast [38], and humans [39], is a novel iron-binding protein [40]
Summary
CyaY, bacterial frataxin ortholog; apoCyaY, CyaY devoid of any iron; apoIscA, IscA devoid of any iron; IscU, a proposed ironsulfur cluster assembly scaffold protein; IscS, cysteine desulfurase. The iron center in IscA can be readily mobilized by L-cysteine [42] and transferred for the iron-sulfur cluster assembly in a proposed scaffold protein IscU (40 – 44). To further elucidate the role of frataxin/CyaY and IscA in biogenesis of iron-sulfur clusters, here we have compared the iron binding property of IscA and CyaY from E. coli under physiological and oxidative stress conditions. The possible physiological role of IscA and CyaY in biogenesis of iron-sulfur clusters and in the intracellular iron metabolism under oxidative stresses will be discussed
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