Eimaan Bilal, Class of 2028

Cysteine (Cys) is a sulfur-containing amino acid found in crystallin proteins that compose our eye’s lens. When Cys is oxidized, it can lead to crystallin protein misfolding and unwanted disulfide bonding, causing light-scattering aggregation. Light-scattering aggregation in crystallin proteins is one of the main contributors to cataract disease, which clouds the lens and can even develop into blindness. Since Cys oxidation can cause misfolding and unwanted disulfide bonding, it is expected that lens proteins would contain smaller amounts of it. Surprisingly, γ-crystallins, a major class of structural lens proteins, are unusually rich in Cys. Dr. Serebryany from Stony Brook University and his colleagues aim to investigate this, hypothesizing that high Cys content may be rooted in evolutionary adaptation. They propose that Cys plays a functional role in maintaining long-term lens transparency while maximizing optical power through a high refractive index.

To explore this, the team used a combination of computational, evolutionary, and structural approaches. They first conducted phylogenetic clustering of γ-crystallin sequences from various vertebrates to explore evolutionary relationships. They organized their findings into a tree diagram that grouped proteins based on sequence similarity.  Then, to examine the structural significance of Cys, the team used D-I-TASSER, a machine learning tool, to predict γ-crystallin structures and analyze solvent accessibility of Cys residues. This allowed them to identify which Cys sites were surface-exposed and potentially involved in redox-driven aggregation.  

Their analysis revealed that the positioning of Cys residues is more functionally significant than the total number present. Certain Cys motifs, such as the DCDCDC loop in γS-crystallins, served as stronger indicators for protein classification than proteomic labels. Additionally, they found that most γ-crystallins expose Cys residues on either the N-terminal or C-terminal domains rather than distributing them across both domains or other structural regions. This selective exposure is likely an evolutionary adaptation to reduce larger disulfide-linked aggregation.    

These findings suggest that γ-crystallins evolved under competing pressures to maintain transparency while maximizing optical performance. The refractive index, a measure of how much a substance bends light, is critical for the lens’s ability to focus light onto the retina. The enrichment of sulfur-containing and aromatic residues, along with the precise spatial arrangement of Cys, reflects the delicate balance between protein stability and high refractive power. This work provides new insights into the major causes of cataract formation and may inform future strategies for therapeutic intervention.

Figure 1: Close-up image of an eye.

Works Cited: 

[1] Serebryany, E., Martin, R. W., & Takahashi, G. R. (2024). The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins. Biomolecules, 14(5), 594–594. https://doi.org/10.3390/biom14050594

[2] Image retrieved from: https://www.pexels.com/photo/close-up-photo-of-unpaired-brown-eye-853457/