Distinct Hydration Properties of Wild-Type and Familial Point Mutant A53T of α-Synuclein Associated with Parkinson's Disease
Distinct Hydration Properties of Wild-Type and Familial Point Mutant A53T of α-Synuclein Associated with Parkinson's Disease
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DOI：
10.1016/j.bpj.2011.08.052
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发表时间：
2011-11-02
影响因子：
3.4
通讯作者：
Tompa, P.
中科院分区：
文献类型：
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作者：
Hazy, E.;Bokor, M.;Tompa, P.
α-突触核蛋白形成淀粉样蛋白的倾向在帕金森病中起着重要作用。三种家族突变 A30P、E46K 和 A53T 与帕金森病相关。因此，揭示这些突变的结构效应对于理解该疾病的分子基础具有基本意义。在这里，我们通过结合宽线核磁共振、差示扫描量热法和分子动力学模拟来比较野生型 α-突触核蛋白及其 A53T 突变体的水合细节来解决这个问题。所有这三种方法都表明水合物壳与两种蛋白质的很大程度上无序状态相容。然而，其细节有所不同，突变体表现出较高水平的水合，表明倾向于更开放的结构，有利于蛋白质-蛋白质相互作用，导致淀粉样蛋白形成。这些差异在淀粉样蛋白状态下消失，表明无论初始单体状态如何，表面拓扑结构基本相同。
The propensity of alpha-synuclein to form amyloid plays an important role in Parkinson's disease. Three familial mutations, A30P, E46K, and A53T, correlate with Parkinson's disease. Therefore, unraveling the structural effects of these mutations has basic implications in understanding the molecular basis of the disease. Here, we address this issue through comparing details of the hydration of wild-type alpha-synuclein and its A53T mutant by a combination of wide-line NMR, differential scanning calorimetry, and molecular dynamics simulations. All three approaches suggest a hydrate shell compatible with a largely disordered state of both proteins. Its fine details, however, are different, with the mutant displaying a somewhat higher level of hydration, suggesting a bias to more open structures, favorable for protein-protein interactions leading to amyloid formation. These differences disappear in the amyloid state, suggesting basically the same surface topology, irrespective of the initial monomeric state.