Frataxin is a highly conserved mitochondrial protein whose deficiency in humans results in Friedreich's ataxia (FRDA), an autosomal recessive disorder characterized by progressive ataxia and cardiomyopathy. Although its cellular function is still not fully clear, the fact that frataxin plays a crucial role in Fe–S assembly on the scaffold protein Isu is well accepted. In the present paper, we report the characterization of eight frataxin variants having alterations on two putative functional regions: the α1/β1 acidic ridge and the conserved β-sheet surface. We report that frataxin iron-binding capacity is quite robust: even when five of the most conserved residues from the putative iron-binding region are altered, at least two iron atoms per monomer can be bound, although with decreased affinity. Furthermore, we conclude that the acidic ridge is designed to favour function over stability. The negative charges have a functional role, but at the same time significantly impair frataxin's stability. Removing five of those charges results in a thermal stabilization of ~24 °C and reduces the inherent conformational plasticity. Alterations on the conserved β-sheet residues have only a modest impact on the protein stability, highlighting the functional importance of residues 122–124.
Conformational plasticity of ADAMTS13 in hemostasis and autoimmunity
