Friedreich's ataxia-associated FXN L198R mutant exhibits diminished stability and altered dynamics

SANTIAGO FARAJ; ERNESTO A. ROMAN; MARTÍN ARÁN; MARIANA GALLO; JAVIER SANTOS

san Javier, Tucumán

Congreso; XLI Reunión Anual de la Sociedad Argentina de Biofísica; 2012

Sociedad Argentina de Biofísica

Frataxin (FXN) is a globular α/β protein of 121 residues, which is expressed in the cytoplasm and imported into themitochondria where it binds Fe metal ions. It acts as an iron chaperon delivering Fe (II) to enzyme partners during heme andFe-S cluster biosynthesis. The structure of human FXN is known by NMR and crystallography (Figure 1A).Variations on the C-terminal region (CTR) correlate with the conformation stability of different homologues (e.g. yeast, E. coli,human). Our previous results indicate that the CTR is a crucial element in the stabilization of FXN (Figure 1B), through theinteraction between apolar residues in the CTR (L198, L200, L203, Y205) and a network of hydrophobic side chains fromboth α-helices in the core of the protein. The presence of this stretch of residues enables this macromolecule to smoothlymodulate its stability and dynamics. These motions may play a key role in the protein function given that the existence ofpoint mutations in this region leads to the development of Friedreich?s ataxia.