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.

Condo', I., Ventura, N., Malisan, F., Rufini, A., Tomassini, B., Testi, R. (2007). In vivo maturation of human frataxin. HUMAN MOLECULAR GENETICS, 16(13), 1534-1540 [10.1093/hmg/ddm102].

In vivo maturation of human frataxin

CONDO', IVANO;MALISAN, FLORENCE;RUFINI, ALESSANDRA;TESTI, ROBERTO
2007-07-01

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.
1-lug-2007
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/04 - PATOLOGIA GENERALE
English
Con Impact Factor ISI
cell line; cells, cultured; mutation; friedreich ataxia; aconitate hydratase; fibroblasts; homozygote; humans; iron-binding proteins; gene expression regulation; molecular sequence data; gene deletion; models, biological; amino acid sequence; lymphocytes
Condo', I., Ventura, N., Malisan, F., Rufini, A., Tomassini, B., Testi, R. (2007). In vivo maturation of human frataxin. HUMAN MOLECULAR GENETICS, 16(13), 1534-1540 [10.1093/hmg/ddm102].
Condo', I; Ventura, N; Malisan, F; Rufini, A; Tomassini, B; Testi, R
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/8805
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