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Article Dans Une Revue Biochemical Journal Année : 2006

Conformational stability of human frataxin and effect of Friedreich‘s ataxia-related mutations on protein folding

Ana R. Correia
  • Fonction : Auteur
Salvatore Adinolfi
  • Fonction : Auteur
Annalisa Pastore
  • Fonction : Auteur
Cláudio M. Gomes
  • Fonction : Auteur

Résumé

The neurodegenerative disorder Friedreich's Ataxia (FRDA) results from a deficiency in frataxin, a putative iron chaperon, and is due to the presence of a high number of GAA repeats in the coding regions of both alleles of the frataxin gene, which impair protein expression. However, some FRDA patients are heterozygous for this triplet expansion, and contain a deleterious point mutation on the other allele. Here we investigate if two particular FRDA-associated frataxin mutants, I154F and W155R, result in unfolded protein as consequence of a severe structural modification. A detailed comparison of the conformational properties of the wild type and mutant proteins combining biophysical and biochemical methodologies was undertaken. We show that the FRDA mutants retain the native fold in physiological conditions but are differentially destabilised as reflected both by their reduced thermodynamic stability and a higher tendency towards proteolytic digestion. The I154F mutant has the strongest effect on fold stability as expected by the fact that the mutated residue contributes to the hydrophobic core formation. Functionally, the iron-binding properties of the mutant frataxins are found to be partly impaired. The apparently paradoxical situation of having clinically aggressive frataxin variants which are folded and are only significantly less stable than the wild type form in a given adverse physiological stress condition is discussed and contextualized in terms of a mechanism determining the pathology of FRDA heterozygous.

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Dates et versions

hal-00478547 , version 1 (30-04-2010)

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Ana R. Correia, Salvatore Adinolfi, Annalisa Pastore, Cláudio M. Gomes, Cláudio M. Gomes. Conformational stability of human frataxin and effect of Friedreich‘s ataxia-related mutations on protein folding. Biochemical Journal, 2006, 398 (3), pp.605-611. ⟨10.1042/BJ20060345⟩. ⟨hal-00478547⟩

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