Separating Instability from Aggregation Propensity in γS-Crystallin Variants
Separating Instability from Aggregation Propensity in γS-Crystallin Variants
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DOI：
10.1016/j.bpj.2010.12.3691
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发表时间：
2011-01-19
影响因子：
3.4
通讯作者：
Martin, Rachel W.
中科院分区：
文献类型：
--
作者：
Brubaker, William D.;Freites, J. Alfredo;Martin, Rachel W.
使用分子动力学 (MD) 模拟、圆二色性 (CD) 和动态光散射 (DLS) 测量来研究眼晶状体蛋白 γ S-晶状体蛋白的聚集倾向。野生型蛋白与白内障相关的 G18V 变体和对称相关的 G106V 变体一起进行了研究。 MD模拟表明，局部序列差异导致这两个明显相似的点突变之间的动力学和水合作用存在显着差异。这一发现得到了实验测量的支持，实验测量表明，尽管两种变体似乎大部分在室温下折叠，但两者都表现出增加的聚集倾向。尽管与疾病相关的 G18V 变体不是最不稳定的，但它比野生型或 G106V 变体更容易聚集。这些结果表明，γ S-晶状体蛋白为研究局部未折叠蛋白聚集中的动力学和水合作用提供了一个出色的模型系统。
Molecular dynamics (MD) simulations, circular dichroism (CD), and dynamic light scattering (DLS) measurements were used to investigate the aggregation propensity of the eye-lens protein gamma S-crystallin. The wild-type protein was investigated along with the cataract-related G18V variant and the symmetry-related G106V variant. The MD simulations suggest that local sequence differences result in dramatic differences in dynamics and hydration between these two apparently similar point mutations. This finding is supported by the experimental measurements, which show that although both variants appear to be mostly folded at room temperature, both display increased aggregation propensity. Although the disease-related G18V variant is not the most strongly destabilized, it aggregates more readily than either the wild-type or the G106V variant. These results indicate that gamma S-crystallin provides an excellent model system for investigating the role of dynamics and hydration in aggregation by locally unfolded proteins.