期刊
STRUCTURE
卷 28, 期 7, 页码 733-+出版社
CELL PRESS
DOI: 10.1016/j.str.2020.04.008
关键词
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资金
- European Research Council under the European Union's H2020 Framework Program (2014-2020)/ERC grant [648030]
- Labex EpiGenMed, an Investissements d'avenir'' program [ANR-10-LABX-12-01]
- GPCteR [ANR-17-CE11-0022-01]
- French National Research Agency [ANR-10-INBS-04-01, ANR-10-INBS-05]
- Fondation pour la Recherche Medicale [SPF20150934061]
- Instruct within the Grenoble Partnership for Structural Biology (PSB) [PID: 1552]
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.
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