ROLE OF PROTEIN METHYLATION IN CATARACT FORMATION

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We propose to investigate the role of protein carboxyl methylation in cow and human eye lens function. We will focus on the possibility that this reaction (or the loss thereof) may be a molecular basis of cataractogenesis. We have recently shown that D-aspartyl residues are enzymatically methylated in human erythrocyte membrane and cytoskeletal proteins. This modification of aspartyl residues with abnormal stereoconfiguration by erythrocyte protein carboxyl methyltransferase may be a step in a protein repair pathway in these cells. Since D-aspartate has been found to accumulate in human lens proteins, and since lenses with brunescent cataracts (but not yellow cataracts) contain exceptionally high levels of D-aspartyl residues, we suspect that if the lens contains a similar protein repair pathway, then it loses efficiency with age and during certain forms of cataract development. Our preliminary results have indicated that, indeed, cow and human lenses contain protein carboxyl methyltransferase activity similar to that in the erythrocyte. We have also found that lenses with brunescent cataracts are highly deficient in this activity compared to that in normal lenses or lenses with yellow cataracts. We now intend to characterize the protein carboxyl methyltransferase in bovine lenses and in normal and cataractous human lenses. We will determine which proteins are methylated in these different lenses, and will be especially interested in the comparison between methyl acceptor proteins in normal and cataractous lenses. We will define the function and regulation of the protein carboxyl methylation pathway in normal lenses and will thus determine whether the failure of this pathway to function can affect the course of aging and cataract development in human lenses.