Human Molecular Genetics, 2002, Vol. 11, No. 16 1865-1877
© 2002 Oxford University Press
A structural approach to understanding the iron-binding properties of phylogenetically different frataxins
1National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK, 2Dipartmento di Chimica, Universitá di Napoli, via Cinthia, Napoli 80126, Italy and 3Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina 45110, Greece
Received April 18, 2002; Accepted June 10, 2002
Friedreich's ataxia (FRDA), an autosomal recessive cardio- and neurodegenerative disease, is caused by low expression of frataxin, a small mitochondrial protein, encoded in the nucleus. At the biochemical level, the lack of frataxin leads to dysregulation of mitochondrial iron homeostasis and oxidative damage, which eventually causes neuronal death. It is, however, still unclear whether frataxin is directly involved in iron binding, since the yeast orthologue, but not the human protein, has been shown to form large aggregates in the presence of large iron excess. We have compared the properties of three proteins from the frataxin family—the bacterial CyaY from Escherichia coli, the yeast Yfh1 and human frataxin—as representative of organisms of increasing complexity. We show that the three proteins have the same fold but different thermal stabilities and iron-binding properties. While human frataxin has no tendency to bind iron, CyaY forms iron-promoted aggregates with a behaviour similar to that of yeast frataxin. However, aggregation can be competed by chelator agents or by ionic strength. At physiological salt conditions, almost no aggregation is observed. The design of mutants produced to identify the protein surface involved in iron-promoted aggregation allows us to demonstrate that the process is mediated by a negatively charged surface ridge. Mutation of three of these residues is sufficient to convert CyaY in a protein with properties similar to those of human frataxin. On the other hand, mutation of the exposed surface of the ß sheet, which contains most of the conserved residues, does not affect aggregation, suggesting that iron binding is a non-conserved part of a more complex cellular function of frataxins.
* To whom correspondence should be addressed. Tel: +44 2089593666; Fax: +44 2089064477; Email: apastore{at}nimr.mrc.ac.uk
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