Protein environment : A crucial triggering factor in josephin domain aggregation: The role of 2,2,2-trifluoroethanol
Visentin, Cristina (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Navarro, Susanna (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Grasso, Gianvito (Università della Svizzera italiana. Istituto Dalle Molle di Studi sull'Intelligenza Artificiale (IDSIA))
Regonesi, Maria Elena (Università di Milano-Bicocca. Dipartimento di Biotecnologie e Bioscienze)
Deriu, Marco Agostino (Università della Svizzera italiana. Istituto Dalle Molle di Studi sull'Intelligenza Artificiale (IDSIA))
Tortora, Paolo (Università di Milano-Bicocca. Dipartimento di Biotecnologie e Bioscienze)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Fecha:	2018
Resumen:	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.
Ayudas:	Ministerio de Economía y Competitividad BIO2016-783-78310-R
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Ataxin-3 ; Josephin domain ; 2,2,2-trifluoroethanol ; Amyloid aggregation ; Molecular dynamics ; Protein-cosolvent interaction
Publicado en:	International journal of molecular sciences, Vol. 19, Núm. 8 (August 2018) , art. 2151, ISSN 1422-0067

DOI: 10.3390/ijms19082151
PMID: 30042316

17 p, 3.4 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Instituto de Biotecnología y de Biomedicina (IBB)
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