Structural Model of the Proline-Rich Domain of Huntingtin Exon-1 Fibrils
Structural Model of the Proline-Rich Domain of Huntingtin Exon-1 Fibrils
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DOI：
10.1016/j.bpj.2020.10.010
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发表时间：
2020-11-17
影响因子：
3.4
通讯作者：
Siemer, Ansgar B.
中科院分区：
文献类型：
--
作者：
Falk, Alexander S.;Bravo-Arredondo, Jose M.;Siemer, Ansgar B.
亨廷顿病是一种遗传性神经退行性疾病，由亨廷顿基因第一外显子中的CAG扩增引起。这种扩增导致延长的多聚谷氨酰胺结构域，其增加亨廷顿蛋白外显子-1形成交叉β原纤维的倾向。虽然多聚谷氨酰胺结构域是重要的原纤维的形成，动态的，C-末端富含脯氨酸的结构域（PRD）的亨廷顿蛋白外显子-1构成了原纤维表面的很大一部分。因为潜在的原纤维毒性必须通过原纤维表面与其细胞环境的相互作用来介导，所以我们想要模拟PRD所采用的构象空间。我们运行了800 ns长的PRD分子动力学模拟使用明确的水模型优化的内在无序的蛋白质。这些模拟准确地预测了我们以前的固态NMR数据和新获得的电子顺磁共振双电子-电子共振距离，使我们对其准确性充满信心。模拟结果表明，PRD通常形成一个不完美的聚脯氨酸（聚P）II螺旋构象。PRD内的两个polyP区域在大部分模拟中保持在polyP II螺旋中，而富含脯氨酸的接头区域中的偶然扭结导致PRD结构中的整体弯曲。在第二聚P区末端的甘氨酸的二面角是非常可变的，有效地将高度动态的12个C-末端残基与PRD的其余部分解耦。
Huntington's disease is a heritable neurodegenerative disease that is caused by a CAG expansion in the first exon of the huntingtin gene. This expansion results in an elongated polyglutamine domain that increases the propensity of huntingtin exon-1 to form cross-beta fibrils. Although the polyglutamine domain is important for fibril formation, the dynamic, C-terminal proline-rich domain (PRD) of huntingtin exon-1 makes up a large fraction of the fibril surface. Because potential fibril toxicity has to be mediated by interactions of the fibril surface with its cellular environment, we wanted to model the conformational space adopted by the PRD. We ran 800-ns long molecular dynamics simulations of the PRD using an explicit water model optimized for intrinsically disordered proteins. These simulations accurately predicted our previous solid-state NMR data and newly acquired electron paramagnetic resonance double electron-electron resonance distances, lending confidence in their accuracy. The simulations show that the PRD generally forms an imperfect polyproline (polyP) II helical conformation. The two polyP regions within the PRD stay in a polyP II helix for most of the simulation, whereas occasional kinks in the proline-rich linker region cause an overall bend in the PRD structure. The dihedral angles of the glycine at the end of the second polyP region are very variable, effectively decoupling the highly dynamic 12 C-terminal residues from the rest of the PRD.