Catalysis of cataract-associated human γD crystallin aggregation via dynamic disulfide exchange [article]

Eugene Serebryany, Shuhuai Yu, Sunia A. Trauger, Bogdan Budnik, Eugene I. Shakhnovich
2018 bioRxiv   pre-print
Several mutations in human γD-crystallin (HγD), a long-lived eye lens protein, cause misfolding and aggregation, leading to cataract. Surprisingly, wild-type HγD catalyzes aggregation of its cataract related W42Q variant while itself remaining soluble -- the inverse of the classical prion-like scenario whereby misfolded polypeptides catalyze aggregation of natively folded ones. The search for a biochemical mechanism of catalysis of W42Q aggregation by WT has revealed that WT HγD can transfer a
more » ... isulfide bond to the W42Q variant. The transferred disulfide kinetically traps an aggregation-prone intermediate made accessible by the W42Q mutation, facilitating light-scattering aggregation of the W42Q variant. The aggregating variant thus becomes a disulfide sink, removing the disulfides from solution. Such redox "hot potato" competitions among wild-type and mutant or modified polypeptides may be relevant for many long-lived proteins that function in oxidizing environments. In these cases aggregation may be forestalled by inhibiting disulfide flow toward damaged polypeptides.
doi:10.1101/300608 fatcat:s26yjsh6dfhmtfzme3bpxmkz6y