Molecular Structure and Function of Crystallins

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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 b- and g-crystallins are still unknown. gS-crystallin is the major bg-crystallin in the adult human lens. Ablation of the gene for gS leads 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 suggests important roles for flexible linker and N-terminal regions in providing entropic contributions to protein solubility. The structure of gS associated with the Opj cataract is also being determined. 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. We have also defined the repertoire of crystallins in an important animal model, the zebrafish and have shown that in this species there has been a gene duplication and separation of functions in aB-crystallin. This demonstrates an important mechanism for the generation of diversity and complexity in vertebrate evolution.