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Human Molecular Genetics Advance Access published online on April 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm102
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

In vivo maturation of human frataxin

Ivano Condò1, Natascia Ventura1, Florence Malisan1, Alessandra Rufini1, Barbara Tomassini1 and Roberto Testi1,2,*

1 Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Italy 2 Fondazione S. Lucia, Rome, Italy

* Correspondence: Prof. Roberto Testi, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy, Phone: +39 0672596503, Fax: +39 0672596505, Email: roberto.testi{at}uniroma2.it

Received December 21, 2006; Revised March 2, 2007; Accepted April 12, 2007

The defective expression of frataxin causes the hereditary neurodegenerative disorder Friedreich's Ataxia (FRDA). Human frataxin is synthesized as a 210 aminoacids (aa) 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 aa mature form, corresponding to residues 56-210 (frataxin56-210). 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 aa protein (frataxin81-210). This maturation product corresponds to the endogenous frataxin detected in human heart, peripheral blood lymphocytes or dermal fibroblasts. Moreover, we demonstrate that frataxin81-210 is biologically functional, as it rescues aconitase defects in frataxin deficient cells derived from FRDA patients. Importantly, our data indicate that frataxin56-210 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.


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