Journal
BIOCHEMISTRY
Volume 57, Issue 33, Pages 4959-4962Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.8b00436
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Funding
- National Council for Science and Technology in Mexico (CONACYT) [221134, PN2076]
- MIT-Seed Funds, National Institutes of Health [EY015834]
- Fulbright-Garcia Robles fellowship
- Catedra Marcos Moshinsky
- National Council for Science and Technology in Mexico
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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.
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