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- W2891468774 endingPage "18009" @default.
- W2891468774 startingPage "17997" @default.
- W2891468774 abstract "Increased light scattering in the eye lens due to aggregation of the long-lived lens proteins, crystallins, is the cause of cataract disease. Several mutations in the gene encoding human γD-crystallin (HγD) cause misfolding and aggregation. Cataract-associated substitutions at Trp42 cause the protein to aggregate in vitro from a partially unfolded intermediate locked by an internal disulfide bridge, and proteomic evidence suggests a similar aggregation precursor is involved in age-onset cataract. Surprisingly, WT HγD can promote aggregation of the W42Q variant while itself remaining soluble. Here, a search for a biochemical mechanism for this interaction has revealed a previously unknown oxidoreductase activity in HγD. Using in vitro oxidation, mutational analysis, cysteine labeling, and MS, we have assigned this activity to a redox-active internal disulfide bond that is dynamically exchanged among HγD molecules. The W42Q variant acts as a disulfide sink, reducing oxidized WT and forming a distinct internal disulfide that kinetically traps the aggregation-prone intermediate. Our findings suggest a redox hot potato competition among WT and mutant or modified polypeptides wherein variants with the lowest kinetic stability are trapped in aggregation-prone intermediate states upon accepting disulfides from more stable variants. Such reactions may occur in other long-lived proteins that function in oxidizing environments. In these cases, aggregation may be forestalled by inhibiting disulfide flow toward mutant or damaged polypeptides." @default.
- W2891468774 created "2018-09-27" @default.
- W2891468774 creator A5018484860 @default.
- W2891468774 creator A5047481335 @default.
- W2891468774 creator A5063451940 @default.
- W2891468774 creator A5077704522 @default.
- W2891468774 creator A5082765817 @default.
- W2891468774 date "2018-11-01" @default.
- W2891468774 modified "2023-10-10" @default.
- W2891468774 title "Dynamic disulfide exchange in a crystallin protein in the human eye lens promotes cataract-associated aggregation" @default.
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