Wild-type Human {gamma}D Crystallin Promotes Aggregation of Its Oxidation-mimicking, Misfolding-prone W42Q Mutant [Molecular Bases of Disease]

March 18th, 2015 by Serebryany, E., King, J. A.

Non-native protein conformers generated by mutation or chemical damage template aggregation of wild-type, undamaged polypeptides in diseases ranging from amyotrophic lateral sclerosis to cancer. We tested for such interactions in the natively monomeric human eye lens protein γD-crystallin, whose aggregation leads to cataract disease. The oxidation-mimicking W42Q mutant of γD-crystallin formed non-native polymers starting from a native-like state under physiological conditions. Aggregation occurred in the temperature range 35-45oC in which the mutant protein began to lose the native conformation of its N-terminal domain. Surprisingly, wild-type γD-crystallin promoted W42Q polymerization in a catalytic manner, even at mutant concentrations too low for homogeneous nucleation to occur. Presence of wild-type protein also downshifted the temperature range of W42Q aggregation. W42Q aggregation required formation of a non-native intramolecular disulfide bond, but not intermolecular cross-linking. Transient WT/W42Q binding may catalyze this oxidative misfolding event in the mutant. That a more-stable variant in a mixture can specifically promote aggregation of a less-stable one rationalizes how extensive aggregation of rare damaged polypeptides can occur during the course of aging.
  • Posted in Journal of Biological Chemistry, Publications
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