Chemical Properties Determine Solubility and Stability in βγ‐Crystallins of the Eye Lens

βγ‐Crystallins are the primary structural and refractive proteins found in the vertebrate eye lens. Because crystallins are not replaced after early eye development, their solubility and stability must be maintained for a lifetime, which is even more remarkable given the high protein concentration in the lens. Aggregation of crystallins caused by mutations or post‐translational modifications can reduce crystallin protein stability and alter intermolecular interactions. Common post‐translational modifications that can cause age‐related cataracts include deamidation, oxidation, and tryptophan derivatization. Metal ion binding can also trigger reduced crystallin solubility through a variety of mechanisms. Interprotein interactions are critical to maintaining lens transparency: crystallins can undergo domain swapping, disulfide bonding, and liquid‐liquid phase separation, all of which can cause opacity depending on the context. Important experimental techniques for assessing crystallin conformation in the absence of a high‐resolution structure include dye‐binding assays, circular dichroism, fluorescence, light scattering, and transition metal FRET. Clear as crystallin? βγ‐crystallins serve as structural and refractive proteins in the vertebrate lens. Mutations in these proteins are associated with cataracts. Herein, we review recent developments toward understanding the biophysical properties and chemical reactivity of monomeric and oligomeric βγ crystallins, including a discussion of the common techniques used to study crystallin structure and stability.