ArticleProtein science : a publication of the Protein Society2020
Cumulative deamidations of the major lens protein γS-crystallin increase its aggregation during unfolding and oxidation.
Article in Protein science : a publication of the Protein Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 45 citations in OpenAlex.
- Dimerization of natively folded molecules drives misfolding and aggregation in Cys-depleted variants of cataract-associated human lens γD-crystallin.The Journal of biological chemistry · 2026Article
- Deamidation Promotes AGE-Modifications in Human Lens γS-Crystallin.Biochemistry · 2026Article
- Mimicking oxidative damage in γS-crystallin with site-specific incorporation of 5-hydroxytryptophan.Biophysical reports · 2026Article
- Lens aging and disease: Molecular mechanisms, functional consequences, and pharmacological implications.Progress in retinal and eye research · 2026Review
- Isomerized and Racemized Aspartyl and Deamidated Asparagine Residues Identified in ɣS-Crystallin.Chembiochem : a European journal of chemical biology · 2025Article
- Identification of Age- and Cataract-Related Changes in High-Density Lens Protein Aggregates.Investigative ophthalmology & visual science · 2025Article
- The Eye Lens Protein, γS Crystallin, Undergoes Glutathionylation-Induced Disulfide Bonding Between Cysteines 22 and 26.Biomolecules · 2025Article
- Isoaspartate-containing galanin in rat hypothalamus.Communications chemistry · 2025Article
- Measurement of absolute abundance of crystallins in human and αA N101D transgenic mouse lenses usingExperimental eye research · 2024Article
- Oxidative Stress in Cataract Formation: Is There a Treatment Approach on the Horizon?Antioxidants (Basel, Switzerland) · 2024Review
- Oxidative Stress and Cataract Formation: Evaluating the Efficacy of Antioxidant Therapies.Biomolecules · 2024Review
- Cumulative asparagine to aspartate deamidation fails to perturb γD-crystallin structure and stability.Protein science : a publication of the Protein Society · 2024Article
- Stability of Protein Pharmaceuticals: Recent Advances.Pharmaceutical research · 2024Review
- Review
- The α-crystallin Chaperones Undergo a Quasi-ordered Co-aggregation Process in Response to Saturating Client Interaction.Journal of molecular biology · 2024Article
- Oxidative stress in the eye and its role in the pathophysiology of ocular diseases.Redox biology · 2023Review
- Eye lens β-crystallins are predicted by native ion mobility-mass spectrometry and computations to form compact higher-ordered heterooligomers.Structure (London, England : 1993) · 2023Article
- Role of Oxidative Stress in Ocular Diseases: A Balancing Act.Metabolites · 2023Review
- Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress.Frontiers in molecular biosciences · 2023Article
- Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens.The Journal of biological chemistry · 2022Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
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 dynamics simulations predicted that deamidation augments the conformational dynamics of γS. We suggest that these perturbations disrupt the native disulfide arrangement of γS and promote the formation of disulfide-linked aggregates. The lens-specific chaperone αA-crystallin was poor at preventing the aggregation of the triple mutant. It is concluded that surface deamidations cause minimal structural disruption individually, but cumulatively they progressively destabilize γS-crystallin leading to unfolding and aggregation, as occurs in aged and cataractous lenses.
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