Human Frataxin Folds Via an Intermediate State. Role of the C-Terminal Region

GONZALEZ-LEBRERO RM; ROMAN EA; FARAJ SE; SANTOS J

Scientific Reports

Nature Publishing Group

Lugar: London; Año: 2016

2045-2322

The aim of this study is to investigate the folding reaction of human frataxin, whose deficiencycauses the neurodegenerative disease Friedreich?s Ataxia (FRDA). The characterization of differentconformational states would provide knowledge about how frataxin can be stabilized without alteringits functionality. Wild-type human frataxin and a set of mutants, including two highly destabilizedFRDA-associated variants were studied by urea-induced folding/unfolding in a rapid mixing device andfollowed by circular dichroism. The analysis clearly indicates the existence of an intermediate state(I) in the folding route with significant secondary structure content but relatively low compactness,compared with the native ensemble. However, at high NaCl concentrations I-state gains substantialcompaction, and the unfolding barrier is strongly affected, revealing the importance of electrostaticsin the folding mechanism. The role of the C-terminal region (CTR), the key determinant of frataxinstability, was also studied. Simulations consistently with experiments revealed that this stretchis essentially unstructured, in the most compact transition state ensemble (TSE2). The completetruncation of the CTR drastically destabilizes the native state without altering TSE2. Results presentedhere shed light on the folding mechanism of frataxin, opening the possibility of mutating it to generatehyperstable variants without altering their folding kinetics.