@article {serebryany2018dynamic, title = {Dynamic disulfide exchange in a crystallin protein in the human eye lens promotes cataract-associated aggregation}, journal = {Journal of Biological Chemistry}, volume = {293}, year = {2018}, pages = {17997{\textendash}18009}, publisher = {ASBMB}, 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 vitrooxidation, 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 {\textquotedblleft}hot potato{\textquotedblright} 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.}, url = {http://www.jbc.org/content/293/46/17997.abstract}, author = {Serebryany, Eugene and Yu, Shuhuai and Trauger, Sunia A and Budnik, Bogdan and Shakhnovich, EugeneI.} }