Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism

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Abstract
The huntingtin protein (HTT) contains a polyQ tract preceded by an N-terminal flanking sequence (HTTNT) that contributes to HTT aggregation. Now the role of HTTNT in aggregation is explored in vitro, revealing a complex, multistep pathway initiated when polyQ disrupts HTTNT structure, enhancing the latter's assembly into prefibrillar aggregates. Within these intermediates, subsequent interactions of the polyQ moieties drive further assembly into compact amyloid aggregates. Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTTNT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTTNT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTTNT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTTNT cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTTNT and polyQ. The results indicate unprecedented complexity in how primary sequence controls aggregation within a substantially disordered peptide and have implications for the molecular mechanism of Huntington's disease.