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Open AccessArticle

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

1
Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain
2
Istituto Dalle Molle di Studi sull’Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), CH-6928 Manno, Switzerland
3
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milano, Italy
4
Centro di Neuroscienze di Milano (Neuro-MI), 20126 Milano, Italy
*
Authors to whom correspondence should be addressed.
Current address: Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milan, Italy.
Int. J. Mol. Sci. 2018, 19(8), 2151; https://doi.org/10.3390/ijms19082151
Received: 3 July 2018 / Revised: 18 July 2018 / Accepted: 20 July 2018 / Published: 24 July 2018
The protein ataxin-3 contains a polyglutamine stretch that triggers amyloid aggregation when it is expanded beyond a critical threshold. This results in the onset of the spinocerebellar ataxia type 3. The protein consists of the globular N-terminal Josephin domain and a disordered C-terminal tail where the polyglutamine stretch is located. Expanded ataxin-3 aggregates via a two-stage mechanism: first, Josephin domain self-association, then polyQ fibrillation. This highlights the intrinsic amyloidogenic potential of Josephin domain. Therefore, much effort has been put into investigating its aggregation mechanism(s). A key issue regards the conformational requirements for triggering amyloid aggregation, as it is believed that, generally, misfolding should precede aggregation. Here, we have assayed the effect of 2,2,2-trifluoroethanol, a co-solvent capable of stabilizing secondary structures, especially α-helices. By combining biophysical methods and molecular dynamics, we demonstrated that both secondary and tertiary JD structures are virtually unchanged in the presence of up to 5% 2,2,2-trifluoroethanol. Despite the preservation of JD structure, 1% of 2,2,2-trifluoroethanol suffices to exacerbate the intrinsic aggregation propensity of this domain, by slightly decreasing its conformational stability. These results indicate that in the case of JD, conformational fluctuations might suffice to promote a transition towards an aggregated state without the need for extensive unfolding, and highlights the important role played by the environment on the aggregation of this globular domain. View Full-Text
Keywords: ataxin-3; josephin domain; 2,2,2-trifluoroethanol; amyloid aggregation; molecular dynamics; protein-cosolvent interaction ataxin-3; josephin domain; 2,2,2-trifluoroethanol; amyloid aggregation; molecular dynamics; protein-cosolvent interaction
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MDPI and ACS Style

Visentin, C.; Navarro, S.; Grasso, G.; Regonesi, M.E.; Deriu, M.A.; Tortora, P.; Ventura, S. Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol. Int. J. Mol. Sci. 2018, 19, 2151.

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