His86 from the N-Terminus of Frataxin Coordinates Iron and Is Required for Fe鈥揝 Cluster Synthesis

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• 作者：Leslie E. Gentry ; Matthew A. Thacker ; Reece Doughty ; Russell Timkovich ; Laura S. Busenlehner
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：September 3, 2013
• 年：2013
• 卷：52
• 期：35
• 页码：6085-6096
• 全文大小：675K
• 年卷期：v.52,no.35(September 3, 2013)
• ISSN：1520-4995

文摘

Human frataxin has a vital role in the biosynthesis of iron鈥搒ulfur (Fe鈥揝) clusters in mitochondria, and its deficiency causes the neurodegenerative disease Friedreich鈥檚 ataxia. Proposed functions for frataxin in the Fe鈥揝 pathway include iron donation to the Fe鈥揝 cluster machinery and regulation of cysteine desulfurase activity to control the rate of Fe鈥揝 production, although further molecular detail is required to distinguish these two possibilities. It is well established that frataxin can coordinate iron using glutamate and aspartate side chains on the protein surface; however, in this work we identify a new iron coordinating residue in the N-terminus of human frataxin using complementary spectroscopic and structural approaches. Further, we demonstrate that His86 in this N-terminal region is required for high affinity iron coordination and iron assembly of Fe鈥揝 clusters by ISCU as part of the Fe鈥揝 cluster biosynthetic complex. If a binding site that includes His86 is important for Fe鈥揝 cluster synthesis as part of its chaperone function, this raises the possibility that either iron binding at the acidic surface of frataxin may be spurious or that it is required for protein鈥損rotein interactions with the Fe鈥揝 biosynthetic quaternary complex. Our data suggest that iron coordination to frataxin may be significant to the Fe鈥揝 cluster biosynthesis pathway in mitochondria.