Protein environment: A crucial triggering factor in josephin domain aggregation: The role of 2,2,2-trifluoroethanol

Cristina Visentin, Susanna Navarro, Gianvito Grasso, Maria Elena Regonesi, Marco Agostino Deriu, Paolo Tortora, Salvador Ventura

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. 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.
Original languageEnglish
Article number2151
JournalInternational Journal of Molecular Sciences
Volume19
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • 2,2,2-trifluoroethanol
  • Amyloid aggregation
  • Ataxin-3
  • Josephin domain
  • Molecular dynamics
  • Protein-cosolvent interaction

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