Cataract is the leading cause of blindness in the world, and it is projected to affect 20-30 million people in 2020. Cataracts are formed upon aggregation of lens proteins into high molecular weight complexes, causing light scattering and lens opacity (1). A variety of experimental and etiological studies implicate metals as a potential etiological agent for cataract. Copper and zinc concentrations in the cataractous lenses are increased significantly, as compared to normal lenses (2). The monomeric all β-sheet Human γD (HγD) crystallin is one of the abundant crystallins in the core of the lens and its non-amyloid aggregation is associated with cataracts.1 We find that micromolar concentrations of Cu(II) and Zn(II) ions exert distinct and specific effects on the conformation of HγD, suggesting site-specific interactions. Circular dichroism studies show that Cu(II) induces loss of secondary structure and stability of HγD. Spectroscopic studies demonstrate that Cu(II) ions can bind at more than one site in the protein. Metal binding to the monomer leads to formation of high molecular weight light scattering aggregates. These metal-induced effects occur at micromolar concentrations of metal ion and protein, starting at metal:protein ratios of 1:1. Interestingly, the lens chaperone αB crystallin protected HγD from metal-induced aggregation. Metal-induced aggregation could be a physiologically relevant phenomenon; understanding its mechanism will help elucidate the role of metal ions in the aggregation of human crystallins and their potential involvement in the development of cataracts. This research has been supported by: MIT-Seed Funds, Conacyt (grant # 221134 and fellowship to J.A.D.-C.), NIH EY015834, AMC-FUMEC and Fulbright-Garcia Robles fellowships to L.Q.1. Moureau, L.K.; King A.J. Trends Mol. Med., 2012, 18, 273-2822. Curtis, E.D. Exp. Eye Res., 1983, 37, 639-647