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Noguera, Martín E.; Aran, Martín; Smal, Clara; Vazquez, Diego S.; Herrera, María Georgina; Roman, Ernesto A.; Alaimo, Nadine; Gallo, Mariana; Santos, Javier
Archives of biochemistry and biophysics, 12/2017, Letnik: 636Journal Article
Human frataxin (FXN) is a highly conserved mitochondrial protein involved in iron homeostasis and activation of the iron-sulfur cluster assembly. FXN deficiency causes the neurodegenerative disease Friedreich's Ataxia. Here, we investigated the effect of alterations in loop-1, a stretch presumably essential for FXN function, on the conformational stability and dynamics of the native state. We generated four loop-1 variants, carrying substitutions, insertions and deletions. All of them were stable and well-folded proteins. Fast local motions (ps-ns) and slower long-range conformational dynamics (μs-ms) were altered in some mutants as judged by NMR. Particularly, loop-1 modifications impact on the dynamics of a distant region that includes residues from the β-sheet, helix α1 and the C-terminal. Remarkably, all the mutants retain the ability to activate cysteine desulfurase, even when two of them exhibit a strong decrease in iron binding, revealing a differential sensitivity of these functional features to loop-1 perturbation. Consequently, we found that even for a small and relatively rigid protein, engineering a loop segment enables to alter conformational dynamics through a long-range effect, preserving the native-state structure and important aspects of function. •Loop-1 mutants of frataxin were designed to alter conformational dynamics.•Tertiary structure is mainly unaffected by the mutations.•Mutations result in both local and long-range effects on dynamics.•Iron binding and cysteine desulfurase activation are differentially affected.
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