Molecular Structure and Function of Crystallins

眼睛的组织依赖于严格调控的发育途径和特化蛋白质家族。这些包括晶状体的晶状体蛋白。我们已经证明，在人类和其他物种中，晶状体蛋白是通过从眼睛中预先存在的蛋白质中招募基因的过程而产生的。因此，晶体蛋白是一种多功能蛋白质。虽然许多种类的晶体蛋白的起源和功能已经被阐明，但主要的β和γ晶体蛋白的起源和功能仍然不清楚。GS-晶体蛋白是成人晶状体中主要的β-晶体蛋白。GS基因的去除会导致正常的纤维细胞组织和细胞核加工的破坏。特别是，细胞的特征复杂的交错缺失，这表明了GS对维持细胞结构的关键功能作用。虽然GS的缺失不会导致白内障，但晶状体的光学特性会被破坏，从而丢失成像。小鼠GS-晶体蛋白的协作核磁共振结构分析已经完成并提交发表。 GS似乎在视网膜神经节细胞中也是应激诱导的，其他人已经在与黄斑变性相关的RPE的玻璃体中发现了GS。与KUMC的一个小组合作，正在使用我们的KO小鼠和OPJ突变小鼠在糖尿病模型中检查GS在神经细胞中的作用。 GN是通过基因组学研究发现的一个新的家族成员。它代表了BG超家族进化的中间体，其基因结构结合了β基因和伽马基因家族的特征。在小鼠中，它在小鼠的晶状体、光感受器和RPE中表达，但在人类和黑猩猩中，该基因似乎已经变成假的，可能不表达。这只是人类血统中对晶状体(和眼睛的其他部分)的分子组成进行重大修改的几个例子之一。人类眼病的某些方面可能会受到最近这些进化变化的影响。 在人类和动物模型中，G-晶体蛋白经常与白内障有关。我们发现，小鼠的第三号白内障是由内源性逆转录病毒插入GE-晶体蛋白基因引起的，导致了一种异常蛋白。它还指出了小鼠基因组中活跃的ERV的来源。在NO3中，GE被截断，但与另一个GE突变体Elo不同，这不会通过淀粉样蛋白的沉积导致细胞死亡。因此，这两个非常相似的突变蛋白可能说明了淀粉样蛋白形成过程中的关键决策点。

Tissues of the eye depend on closely regulated developmental pathways and families of specialized proteins. These include the crystallins of the lens. We have shown that in humans and other species, crystallins have arisen by a process of gene recruitment from proteins with pre-existing roles in the eye. Thus crystallins are multifunctional proteins. While the origins and functions of many classes of crystallins have been elucidated, those of the major groups of beta and gamma crystallins are still not clear. gS-crystallin is the major betagamma-crystallin in the adult human lens. Ablation of the gene for gS leads to disruption of normal fiber cell organization and processing of cell nuclei. In particular, the characteristic complex interdigitations of the cells are lost suggesting a key functional role for gS maintenance of cytoarchitecture. Although deletion of gS does not cause cataract, the optical properties of the lens are disrupted so that image formation is lost. A collaborative NMR structure analysis of mouse gS-crystallin has been completed and submitted for publication. gS is also appears to be stress inducible in retinal ganglion cells and has been found by others in Drusen in the RPE associated with macular degeneration. In collaboration with a group at KUMC, the role of gS in neural cells is being examined in a diabetic model using our KO mice and Opj mutant mice. gN is a novel member of the family discovered through genomics studies. It represents an intermediate in the evolution of the bg superfamily withs a gene structure that combines features of both beta- and gamma- gene families. In mouse it is expressed in lens, photoreceptors and RPE in mouse, but in humans and chimps it appears that the gene has become pseudo and may not be expressed. This is just one of several examples of major modifications to the molecular composition of the lens (and other parts of the eye) in the human lineage. Possibly some aspects of human eye disease may be affected by these recent evolutionary changes. g-Crystallins are often associated with cataract in both human and animal models. We have found that the No3 cataract in mice is caused by insertion of an endogenous retrovirus into the gene for gE-crystallin, giving rise to an aberrant protein. It also points to a source of active ERV in the mouse genome. In No3, gE is truncated but unlike another gE mutant, Elo, this does not lead to cell death through deposition of amyloid. The two very similar mutant proteins may thus illustrate key decision points in the process of amyloid formation.