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Huntington’s disease (HD) is caused by a polyglutamine (polyQ) domain that is expanded beyond a critical threshold near the N-terminus of the huntingtin (htt) protein, directly leading to htt aggregation. While full-length htt is a large (on the order of ∼350 kDa) protein, it is proteolyzed into a variety of N-terminal fragments that accumulate in oligomers, fibrils, and larger aggregates. It is clear that polyQ length is a key determinant of htt aggregation and toxicity. However, the flanking sequences around the polyQ domain, such as the first 17 amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, influence other important biochemical properties of the protein and ultimately its role in pathogenesis. Here, we review the impact of Nt17 on htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of posttranslational modifications (PTMs) that occur in Nt17 in HD, and the function of Nt17 as a membrane targeting domain.

The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease