The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for lifelong lens transparency, so one might expect the ubiquitous lens crystallin superfamilies (alpha and beta gamma) to contain little cysteine. Yet, the Cys content of gamma-crystallins is well above the average for human proteins. We review literature relevant to this longstanding puzzle and take advantage of expanding genomic databases and improved machine learning tools for protein structure prediction to investigate it further. We observe remarkably low Cys conservation in the beta gamma-crystallin superfamily; however, in gamma-crystallin, the spatial positioning of Cys residues is clearly fine-tuned by evolution. We propose that the requirements of long-term lens transparency and high lens optical power impose competing evolutionary pressures on lens beta gamma-crystallins, leading to distinct adaptations: high Cys content in gamma-crystallins but low in beta B-crystallins. Aquatic species need more powerful lenses than terrestrial ones, which explains the high methionine content of many fish gamma- (and even beta-) crystallins. Finally, we discuss synergies between sulfur-containing and aromatic residues in crystallins and suggest future experimental directions.