Molecular Structure and Function of Crystallins

晶状体蛋白的分子结构和功能

• 批准号: 7594046
• 负责人: Graeme J Wistow
• 金额: $ 79.18万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594046
• 关键词: Adult; Amyloidosis; Animal Model; Blindness; Cataract; Cell Maturation; Charge; Class; Crystallins; Development; Disease Outcome; Disruption; Endogenous Retroviruses; Equilibrium; Eye; Failure; Family; Genes; Genetic; Human; Hybrids; Individual; Lead; Light; Macular degeneration; Modeling; Molecular Structure; Mouse Strains; Mus; Mutation; N-terminal; Orthologous Gene; Pathway interactions; Phenotype; Process; Processed Genes; Property; Protein-Folding Disease; Proteins; Refractive Indices; Role; Solubility; Structure; Structure of retinal pigment epithelium; Tissues; Yeasts; fiber cell; lens; mutant; research study

g-Crystallins are associated with cataract in both human and animal models. We have found that the murine No3 cataract is due to insertion of an endogenous retrovirus into the gene for gE-crystallin, giving rise to an aberrant protein. The phenotype of No3 is mild compared with similar mutations. This is at least partly due to suppression of levels for gE in the No3 mutant, probably due to effects of the retroviral LTR. However it is also clear that the phenotype is modulated by the genetic background in different mouse strains. This provides a model for the way in which interactions of different genes can produce different disease outcomes in different individuals. gS-crystallin is the major bg-crystallin in the adult human lens and has also been found to be induced in retinal pigment epithelium in models of macular degeneration. The gene for gS has been ablated in mouse, leading to disruption of normal fiber cell maturation. Yeast 2-hybrid experiments to determine interaction partners for gS are in progress. NMR structure analysis of mouse gS-crystallin has shown important roles for flexible linker and N-terminal regions in providing entropic contributions to protein solubility. The structure of mutant gS associated with the mouse Opj cataract is now being determined and is shedding light on the processes of protein unfolding, This has implications for other protein folding diseases such as amyloid diseases. The biophysical properties of crystallins are finely tuned for the requirements of lens in different species. In humans, gC is a major crystallin of the young lens but shows surprisingly low solubility. In contrast the mouse ortholog has high solubility. Examination of gC from the two species has revealed the importance of subtle balances in charge dipoles for the functional roles of crystallins. Disruption of these dipoles could lead to cataract.

在人类和动物模型中，g-晶状体蛋白与白内障有关。我们发现，小鼠No3白内障是由于将内源性逆转录病毒插入gE-晶状体蛋白基因中，从而产生异常蛋白所致。与类似突变相比，No3的表型较温和。这至少部分是由于 No3 突变体中 gE 水平的抑制，可能是由于逆转录病毒 LTR 的影响。然而，同样清楚的是，不同小鼠品系的表型受到遗传背景的调节。这提供了一个模型，说明不同基因的相互作用如何在不同个体中产生不同的疾病结果。 gS-晶状体蛋白是成人晶状体中主要的bg-晶状体蛋白，并且还被发现在黄斑变性模型的视网膜色素上皮中被诱导。 gS 基因在小鼠体内被消除，导致正常纤维细胞成熟的破坏。确定 gS 相互作用伙伴的酵母 2 杂交实验正在进行中。小鼠 gS-晶状体蛋白的 NMR 结构分析表明，柔性接头和 N 末端区域在为蛋白质溶解度提供熵贡献方面发挥着重要作用。与小鼠 Opj 白内障相关的突变 gS 的结构现已确定，并揭示了蛋白质展开的过程，这对其他蛋白质折叠疾病（如淀粉样蛋白疾病）具有影响。 晶状体蛋白的生物物理特性根据不同物种晶状体的要求进行了微调。在人类中，gC 是年轻晶状体的主要晶状体蛋白，但其溶解度却出人意料地低。相反，小鼠直系同源物具有高溶解度。对这两个物种的 gC 的检查揭示了电荷偶极子的微妙平衡对于晶状体蛋白功能作用的重要性。这些偶极子的破坏可能导致白内障。