Eugene Serebryany Research

Cataract is a protein misfolding disorder resulting from formation of light-scattering aggregates of proteins from the cyrstallin family. These long-lived proteins account for 90% of all protein in the human eye lens. The γD crystallin consists of two symmetrical domains, each of which has a duplicated Greek key fold. Maintaining this topologically complex native fold of the γD cyrstallin is essential for lens transparency. A number of point mutants in the γD crystallin gene cause early-onset cataract. UV-B exposure accelerates cataract onset, and UV irratiation of purified wild-type γD results in aggregation in vitro. A distinctive feature of the Greek key fold is the presence of highly conserved buried tryptophans. Replacements of tryptophan by charged glutamate groups may represent a model of UV-induced photodamge -- intorduction of a charged group into the hydrophobic core generating "denaturation from within." We show that such Trp>Glu mutants can display vastly increased aggregation propensity uder physiological conditions in vitro. Furthermore, a striking property of these mutants is their ability to drive the wild-type protein into the aggregated state. Domain swapping mechanisms can account for this aggregation behavior.