INVESTIGADORES
HERRERA Maria Georgina
artículos
Título:
Insights on the conformational dynamics of human frataxin through modifications of loop-1
Autor/es:
NOGUERA, MARTÍN E.; ARAN, MARTÍN; SMAL, CLARA; VAZQUEZ, DIEGO S.; HERRERA, MARÍA GEORGINA; ROMAN, ERNESTO A.; ALAIMO, NADINE; GALLO, MARIANA; SANTOS, JAVIER
Revista:
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Editorial:
ELSEVIER SCIENCE INC
Referencias:
Año: 2017 vol. 636 p. 123 - 137
ISSN:
0003-9861
Resumen:
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.