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.

亨廷顿氏病的病原体是亨廷顿蛋白（httex1）N端区域的poly-Q同源重复序列，两侧是一个17个残基长的片段（N17）和一个富含脯氨酸的区域（PRR），尚不清楚的机制分别促进和抑制蛋白质的聚集倾向。基于从现场特定标记的NMR样品获得的实验数据，我们得出了httex1的整体模型，该模型将两个侧翼区域都识别为相对的poly-Q二级结构启动子。N17通过涉及Q链中第一个谷氨酰胺侧链的混杂氢键网络触发螺旋性时，PRR促进了相邻谷氨酰胺中的扩展构象。此外，对人类蛋白质组进行的生物信息学分析表明，这些结构特征存在于许多富含谷氨酰胺的人类蛋白质中，并且在具有较长多Q链的蛋白质中更普遍。综上所述，这些观察结果为理解httex1以前的生物物理和功能数据提供了结构基础。