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 (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.