Lens cataracts impair vision and affect 50% of the American population over age 75. Crystallins constitute the most abundant proteins in the eye lens, they are responsible for maintaining the transparency of the lens, and their aggregation is associated to the formation of cataracts. The aggregation of lens crystallins has also been associated to oxidative stress. aA-crystallin, the most abundant crystallin in the human lens, functions as a molecular chaperone by preventing the aggregation of denatured proteins, such as gD-crystallin. aA-crystallin also binds copper ions and prevents copper-induced production of oxidative species. A region of aA-crystallin, encompassing residues 70-88, is associated to its chaperone activity and copper binding properties. Also, aA-crystallin binding to gD-crystallin decreases its copper binding ability. Thus, the specific interaction of copper with a-crystallins is important to understand the interplay between their chaperone activity, copper homeostasis, protein aggregation and copper-induced oxidative stress; however, the structural details of this copper binding site has not been elucidated. The specific aims of this project are: 1) to study the interaction of copper with a-crystallins, using spectroscopic tools to elucidate the nature of the copper-crystallin complex; 2) to evaluate how this interaction affects the redox activity of copper; and 3) to understand how copper binding to a-crystallin affects its interaction with gD-crystallin. Advancing our understanding of copper binding to crystallins should shed light into how this interaction relates to oxidative damage and protein aggregation in the human lens.
For King Lab publications on this topic, look under the Lens Crystallins categorie of the Publication by Category webpage.