Abstract
The causative agent of Huntington's disease, the poly-Q homo-repeat in the N-terminal region of huntingtin (httex1), is flanked by a 17-residue-long fragment (N17) and a proline-rich region (PRR), which promote and inhibit the aggregation propensity of the protein, respectively, by poorly understood mechanisms. Based on experimental data obtained from site-specifically labeled NMR samples, we derived an ensemble model of httex1 that identified both flanking regions as opposing poly-Q secondary structure promoters. While N17 triggers helicity through a promiscuous hydrogen bond network involving the side chains of the first glutamines in the poly-Q tract, the PRR promotes extended conformations in neighboring glutamines. Furthermore, a bioinformatics analysis of the human proteome showed that these structural traits are present in many human glutamine-rich proteins and that they are more prevalent in proteins with longer poly-Q tracts. Taken together, these observations provide the structural bases to understand previous biophysical and functional data on httex1.