Molecular Structure and Function of Crystallins

在人类和动物模型中，G-晶体蛋白都与白内障有关。我们发现，小鼠3号白内障是由于内源性逆转录病毒插入到GE-晶体蛋白基因中，产生了异常蛋白。与类似的突变相比，N3的表型较轻。这至少部分是由于3号突变体中GE水平的抑制，可能是由于逆转录病毒LTR的影响。然而，很明显，不同品系的小鼠的表型受遗传背景的影响。这为不同基因的相互作用在不同的个体中产生不同的疾病结果提供了一个模型。 GS-晶体蛋白是成人晶状体中主要的BG-晶体蛋白，在黄斑变性模型中也被发现在视网膜色素上皮中被诱导。在小鼠中，GS基因已经被消融，导致正常纤维细胞成熟中断。酵母双杂交实验正在进行中，以确定GS的相互作用伙伴。小鼠GS-晶体蛋白的核磁共振结构分析表明，柔性连接区和N-末端区域在提供蛋白质溶解度的熵贡献中起着重要作用。与小鼠OPJ白内障相关的突变GS的结构现在正在确定，并揭示了蛋白质展开的过程，这对其他蛋白质折叠疾病，如淀粉样疾病也有意义。 晶体蛋白的生物物理性质可以根据不同种类的晶状体的要求进行微调。在人类中，GC是年轻晶状体的主要晶状体蛋白，但溶解度低得令人惊讶。相比之下，小鼠直系同系物具有较高的溶解度。对这两个物种的GC检测揭示了电荷偶极的微妙平衡对晶体蛋白功能作用的重要性。这些偶极子的破坏可能会导致白内障。

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.