Molecular basis for the structural instability of human DJ-1 induced by the L166P mutation associated with Parkinson's disease.
Molecular basis for the structural instability of human DJ-1 induced by the L166P mutation associated with Parkinson's disease.
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DOI：
10.1021/bi800677k
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发表时间：
2008-09-09
期刊：
影响因子：
2.9
通讯作者：
Daggett, Valerie
中科院分区：
文献类型：
--
作者：
Anderson, Peter C.;Daggett, Valerie
DJ-1是一种在体内功能未知的二聚体蛋白。人类DJ-1基因中的突变导致残基166（L166 P）处的亮氨酸被脯氨酸取代，这与早发性帕金森病有关。结构稳定性的缺乏已经排除了L166 P DJ-1多晶型物的原子分辨率结构的实验测定。我们在生理温度下对野生型和L166 P DJ-1多晶型物进行了多重分子动力学（MD）模拟（101/3 μs），以预测L166 P取代的特定结构效应。L166 P破坏α1、α5、α6和α8螺旋，其中α8受到特别严重的破坏。蛋白质稳定性和二聚化的关键二级结构元件在整个二聚体界面上被显著破坏，因为二聚体形成中涉及的疏水表面被扩展。相对于野生型DJ-1，L166 P DJ-1占据了更广泛的结构集合，其中许多对应于扭曲的构象。在L166 P二聚体模型中，取代显著地使二聚体界面不稳定，中断了对于二聚体形成重要的>100个分子间接触。L166 P取代还导致高度保守的半胱氨酸残基（Cys-106）区域的重大扰动，该半胱氨酸残基参与二聚化并且对于DJ-1的拟议伴侣功能至关重要。Cys-106位于距离取代位点16 bp处，表明结构破坏在整个蛋白质中传播。此外，L166 P DJ-1显示出相对于野生型蛋白的疏水表面积的显著增加，这可能解释了突变蛋白聚集的趋势。这些模拟提供了以前研究没有揭示的整个L166 P DJ-1的特定结构扰动的细节。
DJ-1 is a dimeric protein of unknown function in vivo. A mutation in the human DJ-1 gene causing substitution of proline for leucine at residue 166 (L166P) has been linked to early-onset Parkinson’s disease. Lack of structural stability has precluded experimental determination of atomic-resolution structures of the L166P DJ-1 polymorph. We have performed multiple molecular dynamics (MD) simulations (∼1/3 μs) of the wild-type and L166P DJ-1 polymorph at physiological temperature to predict specific structural effects of the L166P substitution. L166P disrupted helices α1, α5, α6 and α8 with α8 undergoing particularly severe disruption. Secondary structural elements critical for protein stability and dimerization were significantly disrupted across the entire dimer interface, as were extended hydrophobic surfaces involved in dimer formation. Relative to wild-type DJ-1, L166P DJ-1 populated a broader ensemble of structures, many of which corresponded to distorted conformations. In a L166P dimer model the substitution significantly destabilized the dimer interface, interrupting >100 intermolecular contacts that are important for dimer formation. The L166P substitution also led to major perturbations in the region of a highly conserved cysteine residue (Cys-106) that participates in dimerization and that is critical for a proposed chaperone function of DJ-1. Cys-106 is located ∼16 Å from the substitution site, demonstrating that structural disruptions propagate throughout the whole protein. Furthermore, L166P DJ-1 showed a significant increase in hydrophobic surface area relative to wild-type protein, possibly explaining the tendency of the mutant protein to aggregate. These simulations provide details about specific structural disturbances throughout L166P DJ-1 that previous studies have not revealed.
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