Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cells

S Büning; A Sharma; S Vachharajani; E Newcombe; A Ormsby; M Gao; D Gnutt; T Vöpel; DM Hatters; S Ebbinghaus

Journal article

Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cells

S Büning, A Sharma, S Vachharajani, E Newcombe, A Ormsby, M Gao, D Gnutt, T Vöpel, DM Hatters, S Ebbinghaus

Physical Chemistry Chemical Physics | ROYAL SOC CHEMISTRY | Published : 2017

DOI: 10.1039/c6cp08167c

Abstract

Huntington's disease is caused by a CAG trinucleotide expansion mutation in the Huntingtin gene that leads to an artificially long polyglutamine sequence in the Huntingtin protein. A key feature of the disease is the intracellular aggregation of the Huntingtin exon 1 protein (Httex1) into micrometer sized inclusion bodies. The aggregation process of Httex1 has been extensively studied in vitro, however, the crucial early events of nucleation and aggregation in the cell remain elusive. Here, we studied the conformational dynamics and self-association of Httex1 by in-cell experiments using laser-induced temperature jumps and analytical ultracentrifugation. Both short and long polyglutamine var..

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University of Melbourne Researchers

Danny M Hatters Author

Related Projects (4)

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Grants

Awarded by Huntington's Disease Society of America

Funding Acknowledgements

Httex1Qn-mCFP/mYFP recombinant plasmids were kind gifts from Toshiaki Takahashi (Niigata, Japan). We thank Martin Gruebele (Urbana-Champaign, USA) for the mpDream2.1 vector and Patrick Lajoie (London, Canada) for the Htt<INF>ex1</INF>Qn-split GFP plasmids. S. E. acknowledges funding from the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia (Ruckkehrerprogramm) and the Cluster of Excellence RESOLV (EXC 1069) funded by the German Research Foundation (DFG). D. M. H. acknowledges funding by grants from the National Health and Medical Research Council (APP1049458 and APP1049459), the Australian Research Council (FT120100039) and the Huntington's Disease Society of America (HDSA), HD Human Biology Project.