Molecular Structure and Function of Crystallins

g-晶体蛋白与人类和动物模型中的白内障相关。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-晶状体蛋白基因中，引起异常蛋白。与相似突变相比，No3的表型是温和的。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的作用。然而，同样清楚的是，在不同的小鼠品系中，表型受到遗传背景的调节。这为不同基因的相互作用在不同个体中产生不同疾病结果的方式提供了一个模型。 gS-晶状体蛋白是成人透镜中主要的bg-晶状体蛋白，并且还发现在黄斑变性模型的视网膜色素上皮中被诱导。在小鼠中，gS基因已被切除，导致正常纤维细胞成熟的破坏。酵母双杂交实验，以确定相互作用的合作伙伴的gS正在进行中。小鼠gS-晶状体蛋白的NMR结构分析显示了柔性接头和N-末端区域在提供蛋白质溶解度的熵贡献中的重要作用。与小鼠Opj白内障相关的突变gS的结构现在正在确定，并且正在揭示蛋白质解折叠的过程，这对其他蛋白质折叠疾病如淀粉样蛋白疾病具有意义。 晶体蛋白的生物物理性质根据不同物种的透镜的要求进行微调。在人类中，gC是年轻透镜的主要晶状体蛋白，但显示出令人惊讶的低溶解度。相反，小鼠直系同源物具有高溶解度。从这两个物种的gC检查揭示了晶体蛋白的功能作用的电荷偶极子的微妙平衡的重要性。这些偶极子的破坏可能导致白内障。

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.