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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cataract-associated mutant E107A of human γD-crystallin shows increased attraction to α-crystallin and enhanced light scattering
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Cataract-associated mutant E107A of human γD-crystallin shows increased attraction to α-crystallin and enhanced light scattering

机译：人类γD-晶状体与白内障相关的突变体E107A显示出对α-晶状体蛋白的吸引力增加和光散射增强

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Several point mutations in human γD-crystallin (HGD) are now known to be associated with cataract. So far, the in vitro studies of individual mutants of HGD alone have been sufficient in providing plausible molecular mechanisms for the associated cataract in vivo. Nearly all the mutant proteins in solution showed compromised solubility and enhanced light scattering due to altered homologous γ-γ crystallin interactions. In sharp contrast, here we present an intriguing case of a human nuclear cataract-associated mutant of HGD-namely Glu107 to Ala (E107A), which is nearly identical to the wild type in structure, stability, and solubility properties, with one exception: Its pI is higher by nearly one pH unit. This increase dramatically alters its interaction with α-crystallin. There is a striking difference in the liquid-liquid phase separation behavior of E107A-α-crystallin mixtures compared to HGD-α-crys-tallin mixtures, and the light-scattering intensities are significantly higher for the former. The data show that the two coexisting phases in the E107A-α mixtures differ much more in protein density than those that occur in HGD-α mixtures, as the proportion of α-crystallin approaches that in the lens nucleus. Thus in HGD-α mixtures, the demixing of phases occurs primarily by protein type while in E107A-α mixtures it is increasingly governed by protein density. Analysis of these results suggests that the cataract due to the E107A mutation could result from the instability caused by the altered attractive interactions between dissimilar proteins -i.e., heterologous γ-α crystallin interactions-primarily due to the change in surface electrostatic potential in the mutant protein.
机译：现在已知人γD-晶状体蛋白（HGD）中的一些点突变与白内障有关。到目前为止，仅对HGD的单个突变体进行的体外研究就足以为体内相关的白内障提供合理的分子机制。溶液中几乎所有的突变蛋白由于改变了同源的γ-γ晶状体蛋白相互作用而显示出溶解度降低和光散射增强的特性。与之形成鲜明对比的是，在这里我们提出了一个有趣的案例，即人类遗传性白内障相关的HGD突变体，即Glu107突变为Ala（E107A），该突变体在结构，稳定性和溶解性方面与野生型几乎相同，但以下情况除外：其pI值高出近一个pH单位。该增加极大地改变了其与α-晶体蛋白的相互作用。与HGD-α-晶体-塔林混合物相比，E107A-α-晶体蛋白混合物的液相-液相分离行为存在显着差异，并且前者的光散射强度明显更高。数据表明，随着α-晶体蛋白的比例接近晶状体核，E107A-α混合物中两个共存相的蛋白质密度相较于HGD-α混合物中存在的相差更大。因此，在HGD-α混合物中，相的分解主要是由蛋白质类型引起的，而在E107A-α混合物中，相的分解越来越受到蛋白质密度的控制。对这些结果的分析表明，E107A突变引起的白内障可能是由于异种蛋白之间有吸引力的相互作用改变（即异源γ-α晶状体相互作用）引起的不稳定性所致，主要是由于突变体蛋白中表面静电势的变化。

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    Priya R. Banerjee; Ajay Pande; Julita Patrosz; George M. Thurston; Jayanti Pande;

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    Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;

    Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;

    Department of Biology, University at Albany, State University of New York, Albany, NY 12222;

    Department of Physics, Rochester Institute of Technology, Rochester, NY 14623;

    Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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