期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 18, 页码 11491-11503出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.621581
关键词
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资金
- National Institutes of Health from the National Eye Institute [EY015834]
- Massachusetts Institute of Technology Biology/Merck academic support fellowships
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 gamma D-crystallin, whose aggregation leads to cataract disease. The oxidation-mimicking W42Q mutant of gamma D-crystallin formed non-native polymers starting from a native-like state under physiological conditions. Aggregation occurred in the temperature range 35-45 degrees C, in which the mutant protein began to lose the native conformation of its N-terminal domain. Surprisingly, wild-type gamma D-crystallin promoted W42Q polymerization in a catalytic manner, even at mutant concentrations too low for homogeneous nucleation to occur. The 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 mis-folding 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.
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