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In vivo maturation of human frataxin

Ivano Condò1, Natascia Ventura, Florence Malisan

  • 1Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.

Human Molecular Genetics
|May 1, 2007
PubMed

Insights

Researchers identified the primary maturation site of frataxin, the protein deficient in Friedreich

Area of Science:

  • Molecular Biology
  • Neurogenetics
  • Mitochondrial Biology

Background:

  • Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by defective frataxin expression.
  • Human frataxin is synthesized as a precursor requiring mitochondrial proteolytic processing for function.
  • Previous in vitro studies suggested a 155 amino acid mature form (frataxin(56-210)).

Purpose of the Study:

  • To investigate frataxin maturation in vivo using human cell overexpression.
  • To identify the primary cleavage site and resulting mature frataxin form.
  • To assess the biological function of the identified mature frataxin.

Main Methods:

  • In vivo overexpression of human frataxin in human cells.
  • Analysis of proteolytic processing and identification of cleavage sites.
  • Functional assessment of mature frataxin in rescuing aconitase defects in FRDA patient-derived cells.

Main Results:

  • The main in vivo mature frataxin form is 130 amino acids (frataxin(81-210)), generated by cleavage between Lys80 and Ser81.
  • This frataxin(81-210) form is detected endogenously in human tissues and cells.
  • Frataxin(81-210) rescues aconitase defects in frataxin-deficient FRDA cells, confirming its biological function.
  • An alternative processing yielding frataxin(56-210) occurs in vivo when the primary cleavage site is absent.

Conclusions:

  • The primary in vivo maturation of human frataxin yields a 130 amino acid protein (frataxin(81-210)).
  • This frataxin(81-210) form is functionally active and relevant to endogenous frataxin.
  • Proteolytic mechanisms can control frataxin maturation size in vivo, with potential functional implications for FRDA.

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