Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation

How do N- and C-terminal flanking sequences from exon 1 of the huntingtin protein modulate the mechanisms of polyglutamine aggregation? We answer this question using approaches that combine distinct probes of aggregation mechanisms with measurements of solubility and aggregate morphologies. The N- and C-terminal flanking sequence modules from exon 1 of huntingtin act as gatekeepers, whereby the N-terminal flanking sequence accelerates fibril formation while destabilizing nonfibrillar species, whereas the C-terminal flanking sequence reduces the overall driving force for aggregation. These results provide a mechanistic underpinning for observations regarding naturally occurring sequence contexts as modulators of polyglutamine toxicity.