Elena-Real Carlos A, Sagar Amin, Urbanek Annika, Popovic Matija, Morató Anna, Estaña Alejandro, Fournet Aurélie, Doucet Christine, Lund Xamuel L, Shi Zhen-Dan, Costa Luca, Thureau Aurélien, Allemand Frédéric, Swenson Rolf E, Milhiet Pierre-Emmanuel, Crehuet Ramon, Barducci Alessandro, Cortés Juan, Sinnaeve Davy, Sibille Nathalie, Bernadó Pau
Centre for Structural Biology, University of Montpellier, INSERM, CNRS, Montpellier, France.
LAAS-CNRS, University of Toulouse, CNRS, Toulouse, France.
Nat Struct Mol Biol. 2023 Mar;30(3):309-320. doi: 10.1038/s41594-023-00920-0. Epub 2023 Mar 2.
Huntington's disease is a neurodegenerative disorder caused by a CAG expansion in the first exon of the HTT gene, resulting in an extended polyglutamine (poly-Q) tract in huntingtin (httex1). The structural changes occurring to the poly-Q when increasing its length remain poorly understood due to its intrinsic flexibility and the strong compositional bias. The systematic application of site-specific isotopic labeling has enabled residue-specific NMR investigations of the poly-Q tract of pathogenic httex1 variants with 46 and 66 consecutive glutamines. Integrative data analysis reveals that the poly-Q tract adopts long α-helical conformations propagated and stabilized by glutamine side chain to backbone hydrogen bonds. We show that α-helical stability is a stronger signature in defining aggregation kinetics and the structure of the resulting fibrils than the number of glutamines. Our observations provide a structural perspective of the pathogenicity of expanded httex1 and pave the way to a deeper understanding of poly-Q-related diseases.
亨廷顿舞蹈症是一种神经退行性疾病，由HTT基因第一外显子中的CAG重复扩增引起，导致亨廷顿蛋白（httex1）中出现延伸的聚谷氨酰胺（poly-Q）序列。由于其固有的灵活性和强烈的组成偏差，当增加聚谷氨酰胺长度时其发生的结构变化仍知之甚少。位点特异性同位素标记的系统应用使得能够对具有46个和66个连续谷氨酰胺的致病性httex1变体的聚谷氨酰胺序列进行残基特异性核磁共振研究。综合数据分析表明，聚谷氨酰胺序列采用由谷氨酰胺侧链与主链氢键传播和稳定的长α-螺旋构象。我们表明，在定义聚集动力学和所得纤维的结构方面，α-螺旋稳定性比谷氨酰胺数量是更强的特征。我们的观察结果提供了关于扩增的httex1致病性的结构观点，并为更深入理解聚谷氨酰胺相关疾病铺平了道路。
