Issue 17, 2017

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

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 variants of Httex1 underwent an apparent temperature-induced conformational collapse. The temperature jumps generated a population of kinetically trapped species selectively for the longer polyglutamine variants of Httex1 proteins. Their occurrence correlated with the formation of inclusion bodies suggesting that such species trigger further self-association.

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

Supplementary files

Article information

Article type
Paper
Submitted
29 Nov 2016
Accepted
09 Jan 2017
First published
09 Jan 2017

Phys. Chem. Chem. Phys., 2017,19, 10738-10747

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, D. M. Hatters and S. Ebbinghaus, Phys. Chem. Chem. Phys., 2017, 19, 10738 DOI: 10.1039/C6CP08167C

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