Insights on the conformational dynamics of human frataxin through modifications of loop-1

NOGUERA, MARTÍN E.; VAZQUEZ, DIEGO S.; ALAIMO, NADINE; NOGUERA, MARTÍN E.; VAZQUEZ, DIEGO S.; ALAIMO, NADINE; SMAL, CLARA; ROMAN, ERNESTO A.; SANTOS, JAVIER; SMAL, CLARA; ROMAN, ERNESTO A.; SANTOS, JAVIER; ARAN, MARTÍN; HERRERA, MARÍA GEORGINA; GALLO, MARIANA; ARAN, MARTÍN; HERRERA, MARÍA GEORGINA; GALLO, MARIANA

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS

ELSEVIER SCIENCE INC

Año: 2017 vol. 636 p. 123 - 137

0003-9861

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.