Mercury ions impact the kinetic and thermal stabilities of human lens ?-crystallins via direct metal-protein interactions

Loss of metal homeostasis may be involved in several age-related diseases, such as cataracts. Cataracts are caused by the aggregation of lens proteins into light-scattering high molecular weight complexes that impair vision. Environmental exposure to heavy metals, such as mercury, is a risk factor for cataract development. Indeed, mercury ions induce the non-amyloid aggregation of human gamma C-and gamma S crystallins, while human gamma D-crystallin is not sensitive to this metal. Using Differential Scanning Calorimetry (DSC), we evaluate the impact of mercury ions on the kinetic stability of the three most abundant human gamma-crystallins. The metal/crystallin interactions were characterized using Isothermal Titration Calorimetry (ITC). Human gamma D-crystallins exhibited kinetic stabi-lization due to the presence of mercury ions, despite its thermal stability being decreased. In contrast, human gamma C-and gamma S-crystallins are both, thermally and kinetically destabilized by this metal, consistent with their sensitivity to mercury-induced aggregation. The interaction of human gamma-crystallins with mercury ions is highly exothermic and complex, since the protein interacts with the metal at more than three sites. The isolated domains of human gamma-D and its variant with the H22Q mutation were also studied, revealing the importance of these regions in the mercury-induced stabilization by a direct metal-protein interaction.

Automated summary

Loss of metal homeostasis may lead to age-related diseases like cataracts, which are caused by lens protein aggregation. Exposure to heavy metals, particularly mercury, increases the risk of cataract development. Mercury ions induce the aggregation of certain lens proteins, while others are not affected. This study investigates the impact of mercury ions on the stability of different lens proteins and reveals the complex metal-protein interactions that contribute to cataract formation.