Conformational dynamics and self-association of intrinsically disordered Huntingtin exon 1 in cellsElectronic supplementary information (ESI) available. See DOI: 10.1039/c6cp08167c

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 (Htt ex1 ) into micrometer sized inclusion bodies. The aggregation process of Htt ex1 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 Htt ex1 by in-cell experiments using laser-induced temperature jumps and analytical ultracentrifugation. Both short and long polyglutamine variants of Htt ex1 underwent an apparent temperature-induced conformational collapse. The temperature jumps generated a population of kinetically trapped species selectively for the longer polyglutamine variants of Htt ex1 proteins. Their occurrence correlated with the formation of inclusion bodies suggesting that such species trigger further self-association. In-cell temperature jump experiments induce monomer collapse, misfolding and self-association of the Huntingtin exon 1 protein.