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Abstract
Analysis of aged and cataract lenses shows the presence of increased amounts of crystallin fragments in the high molecular weight aggregates of water-soluble and water-insoluble fractions. However, the significance of accumulation and interaction of low molecular weight crystallin fragments in aging and cataract development is not clearly understood. In this study, 23 low molecular mass (<3.5-kDa) peptides in the urea-soluble fractions of young, aged, and aged cataract human lenses were identified by mass spectroscopy. Two peptides, alphaB-(1-18) (MDIAIHHPWIRRPFFPFH) and betaA3/A1-(59-74) (SD(N)AYHIERLMSFRPIC), present in aged and cataract lens but not young lens, and a third peptide, gammaS-(167-178) (SPAVQSFRRIVE) present in all three lens groups were synthesized to study the effects of interaction of these peptides with intact alpha-, beta-, and gamma-crystallins and alcohol dehydrogenase, a protein used in aggregation studies. Interaction of alphaB-(1-18) and betaA3/A1-(59-74) peptides increased the scattering of light by beta- and gamma-crystallin and alcohol dehydrogenase. The ability of alpha-crystallin subunits to function as molecular chaperones was significantly reduced by interaction with alphaB-(1-18) and betaA3/A1-(59-74) peptides, whereas gammaS peptide had no effect on chaperone-like activity of alpha-crystallin. The betaA3/A1-(59-74 peptide caused a 5.64-fold increase in alphaB-crystallin oligomeric mass and partial precipitation. Replacing hydrophobic residues in alphaB-(1-18) and betaA3/A1-(59-74) peptides abolished their ability to induce crystallin aggregation and light scattering. Our study suggests that interaction of crystallin-derived peptides with intact crystallins could be a key event in age-related protein aggregation in lens and cataractogenesis.
Highlights
It is hypothesized that cataract develops as a result of the improper interaction of crystallin fragments generated by proteolysis [17], the mechanism by which crystallin fragments initiate or influence the process of lens protein aggregation to form high molecular weight aggregates is not clear
The relative light scattering activity of low molecular weight fractions was estimated by the Alcohol dehydrogenase (ADH) aggregation assay described earlier [32]
Low molecular weight crystallin fragments from the I–IV groups of lenses were concentrated to a final volume of 150 l/lens, and 25-l samples were used in assays
Summary
The present study was performed to identify crystallin fragments in young, aged, and cataract human lenses and investigate their possible role in crystallin aggregation and light scattering. Our data show that peptides generated in the lens interact with crystallins and increase their aggregation and precipitation. The results demonstrate that crystallin peptides generated in vivo exhibit anti-chaperone-like activity
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