title: In vivo maturation of human frataxin.
abstract: The defective expression of frataxin causes the hereditary neurodegenerative disorder Friedreich's ataxia (FRDA). Human frataxin is synthesized as a 210 amino acid precursor protein, which needs proteolytic processing into mitochondria to be converted into the functional mature form. In vitro processing of human frataxin was previously described to yield a 155 amino acid mature form, corresponding to residues 56-210 (frataxin(56-210)). Here, we studied the maturation of frataxin by in vivo overexpression in human cells. Our data show that the main form of mature frataxin is generated by a proteolytic cleavage between Lys80 and Ser81, yielding a 130 amino acid protein (frataxin(81-210)). This maturation product corresponds to the endogenous frataxin detected in human heart, peripheral blood lymphocytes or dermal fibroblasts. Moreover, we demonstrate that frataxin(81-210) is biologically functional, as it rescues aconitase defects in frataxin-deficient cells derived from FRDA patients. Importantly, our data indicate that frataxin(56-210) can be produced in vivo when the primary 80-81 maturation site is unavailable, suggesting the existence of proteolytic mechanisms that can actively control the size of the mature product, with possible functional implications.
authors.affiliation: Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.forename: Natascia
authors.initials: N
authors.lastname: Ventura
authors.forename: Florence
authors.initials: F
authors.lastname: Malisan
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.forename: Barbara
authors.initials: B
authors.lastname: Tomassini
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000595:Amino Acid Sequence; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005621:Friedreich Ataxia / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D033862:Iron-Binding Proteins; D000096923:Frataxin