Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 636, Issue -, Pages 123-137Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2017.10.022
Keywords
Friedreich's ataxia; Conformational dynamics; Backbone motions; Protein engineering
Categories
Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT PICT) [0983]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas
- Universidad de Buenos Aires [UBACyT2014 20020130100468BA]
- FARA, Friedreich's Ataxia Research Alliance
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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 (mu s-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 beta-sheet, helix alpha 1 and the C-terminal. Remarkably, all the mutants retain the ability to activate cysteine de-sulfurase, 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.
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