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 beta 
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.