title: N-terminal iron-mediated self-cleavage of human frataxin: regulation of iron binding and complex formation with target proteins.
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 (alpha1) and the beta-sheet (beta1), 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.
authors.affiliation: Evans Laboratory of Chemistry, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Taejin
authors.initials: T
authors.lastname: Yoon
authors.forename: Eric
authors.initials: E
authors.lastname: Dizin
authors.forename: J A
authors.initials: JA
authors.lastname: Cowan
mesh_terms: D000595:Amino Acid Sequence; D002151:Calorimetry; D006801:Humans; D007501:Iron / Q000737:chemistry* / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013455:Sulfur / Q000378:metabolism; D000096122:Mitochondrial Processing Peptidase; D000096923:Frataxin
chemical_list: D007501:Iron; D033862:Iron-Binding Proteins; D008666:Metalloendopeptidases; D013455:Sulfur; D000096122:Mitochondrial Processing Peptidase; D000096923:Frataxin