Cumulative deamidations of the major lens protein γS-crystallin increase its aggregation during unfolding and oxidation.

Protein Science : a Publication of the Protein Society
Calvin J VetterKirsten J Lampi

Abstract

Age-related lens cataract is the major cause of blindness worldwide. The mechanisms whereby crystallins, the predominant lens proteins, assemble into large aggregates that scatter light within the lens, and cause cataract, are poorly understood. Due to the lack of protein turnover in the lens, crystallins are long-lived. A major crystallin, γS, is heavily modified by deamidation, in particular at surface-exposed N14, N76, and N143 to introduce negative charges. In this present study, deamidated γS was mimicked by mutation with aspartate at these sites and the effect on biophysical properties of γS was assessed via dynamic light scattering, chemical and thermal denaturation, hydrogen-deuterium exchange, and susceptibility to disulfide cross-linking. Compared with wild type γS, a small population of each deamidated mutant aggregated rapidly into large, light-scattering species that contributed significantly to the total scattering. Under partially denaturing conditions in guanidine hydrochloride or elevated temperature, deamidation led to more rapid unfolding and aggregation and increased susceptibility to oxidation. The triple mutant was further destabilized, suggesting that the effects of deamidation were cumulative. Molecular ...Continue Reading

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Citations

Dec 3, 2020·Structure·Alex J GusemanAngela M Gronenborn
Apr 15, 2021·Expert Review of Proteomics·Lee S Cantrell, Kevin L Schey
Jun 3, 2021·Acta Crystallographica. Section D, Structural Biology·Brenna Norton-BakerEike C Schulz
Aug 2, 2021·Experimental Eye Research·Eugene SerebryanyLiliana Quintanar

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