Molecular Structure and Function of Crystallins

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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.