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Artículo

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

Faraj, Santiago EnriqueIcon ; Gonzalez-Lebrero, Rodolfo MartinIcon ; Roman, Ernesto AndresIcon ; Santos, JavierIcon
Fecha de publicación: 02/2016
Editorial: Nature Publishing Group
Revista: Scientific Reports
ISSN: 2045-2322
Idioma: Inglés
Tipo de recurso: Artículo publicado

Resumen

The aim of this study is to investigate the folding reaction of human frataxin, whose deficiency causes the neurodegenerative disease Friedreich’s Ataxia (FRDA). The characterization of different conformational states would provide knowledge about how frataxin can be stabilized without altering its functionality. Wild-type human frataxin and a set of mutants, including two highly destabilized FRDA-associated variants were studied by urea-induced folding/unfolding in a rapid mixing device and followed 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 substantial compaction, and the unfolding barrier is strongly affected, revealing the importance of electrostatics in the folding mechanism. The role of the C-terminal region (CTR), the key determinant of frataxin stability, was also studied. Simulations consistently with experiments revealed that this stretch is essentially unstructured, in the most compact transition state ensemble (TSE2). The complete truncation of the CTR drastically destabilizes the native state without altering TSE2. Results presented here shed light on the folding mechanism of frataxin, opening the possibility of mutating it to generate hyperstable variants without altering their folding kinetics.
Palabras clave: Frataxin , Folding , Stability , Kinetic
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
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URI: http://hdl.handle.net/11336/47255
URL: https://www.nature.com/articles/srep20782
DOI: http://dx.doi.org/10.1038/srep20782
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Articulos(IQUIFIB) [439]
Articulos de INST.DE QUIMICA Y FISICO-QUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Citación
Faraj, Santiago Enrique; Gonzalez-Lebrero, Rodolfo Martin; Roman, Ernesto Andres; Santos, Javier; Human Frataxin Folds Via an Intermediate State. Role of the C-Terminal Region; Nature Publishing Group; Scientific Reports; 6; 2-2016; 1-16; 20782
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