A Histidine Switch for Zn-Induced Aggregation of γ-Crystallins Reveals a Metal-Bridging Mechanism That Is Relevant to Cataract Disease

Cataract disease results from non-amyloid aggregation of eye lens proteins and is the leading cause of blindness in the world. Zinc concentrations in cataractous lenses are increased significantly relative to those in healthy lenses. It was recently reported that Zn(II) ions induce the aggregation of one of the more abundant proteins in the core of the lens, human gamma D-crystallin. Here, the mechanism of Zn-induced aggregation has been revealed through a comparative study of three homologous human lens gamma-crystallins and a combination of spectroscopic, electron microscopy, and site-directed mutagenesis studies. This work reveals that a single His residue acts as a switch for the Zn-induced non-amyloid aggregation of human gamma-crystallins. Aggregation can be reversed by a chelating agent, revealing a metal-bridging mechanism. This study sheds light on an aberrant Zn-crystallin interaction that promotes aggregation, a process that is relevant to cataract disease.