Molecular origin of polyglutamine aggregation in neurodegenerative diseases
Molecular origin of polyglutamine aggregation in neurodegenerative diseases
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DOI：
10.1371/journal.pcbi.0010030
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发表时间：
2005-08-01
影响因子：
4.3
通讯作者：
Dokholyan, NV
中科院分区：
文献类型：
--
作者：
Khare, SD;Ding, F;Dokholyan, NV
蛋白质中聚谷氨酰胺 (polyQ) 束的扩张会导致蛋白质聚集，并与至少九种神经再生性疾病中的细胞死亡相关。疾病发病年龄与高于 35-40 个谷氨酰胺临界值的 PolyQ 插入长度相关。体外分离的 PolyQ 肽的聚集动力学也显示出类似的临界长度依赖性。虽然最近的实验工作对 PolyQ 聚集提供了相当多的见解，但聚集的分子机制尚不清楚。在这里，使用分离的polyQ肽的计算机模拟，我们表明聚集机制是单个polyQ肽链从随机卷曲到平行P螺旋的构象转变。这种转变选择性地发生在长度超过 37 个谷氨酰胺的肽中。在模拟中观察到的P-螺旋中，所有残基均采用P-链主链二面角，并且多肽链围绕中心螺旋轴盘绕，每圈18.5+/-2个残基。我们还发现，具有脯氨酸-甘氨酸插入物的突变体polyQ肽在其基态下显示出反平行β-发夹的形成，这与实验一致。突变型 P-螺旋的稳定性较低，这解释了它们与野生型相比聚集率较低的原因。我们的结果提供了 PolyQ 介导的聚集的分子机制。
Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neuroclegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35-40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel P-helix. This transition occurs selectively in peptides longer than 37 glutamines. in the P-helices observed in simulations, all residues adopt P-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 +/- 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel beta-hairpins in their ground state, in agreement with experiments. The lower stability of mutant P-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation.