N-terminal iron-mediated self-cleavage of human frataxin: regulation of iron binding and complex formation with target proteins |
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Authors: | Taejin Yoon Eric Dizin J A Cowan |
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Institution: | (1) Evans Laboratory of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA |
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Abstract: | Frataxin is an iron-binding mitochondrial matrix protein that has been shown to mediate iron delivery during iron–sulfur cluster
and heme biosynthesis. Mitochondrial processing peptidase (MPP) yields a form of human frataxin corresponding to residues
56–210. However, structural and functional studies have focused on a core structure that results from an ill-defined cleavage
event at the N-terminus. Herein we show that the N-terminus of MPP-processed frataxin shows a unique high-affinity iron site
and that this iron center appears to mediate a self-cleavage reaction. Moreover, the N-terminus appears to block previously
defined iron-binding sites located on the carboxylate-rich surface defined by the helix (α1) and the β-sheet (β1), most likely
through electrostatic contact with the carboxylate-rich surface on the core protein, as well as inhibiting iron-promoted binding
of the iron–sulfur cluster assembly scaffold partner protein, ISU. The physiological significance of iron-mediated release
of the N-terminal residues from this anionic surface is discussed. |
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Keywords: | Frataxin Friedreich’ s ataxia Self-cleavage Iron binding ISU |
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