Molecular Structure and Function of Crystallins

National Eye Institute

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Abstract

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.