ArticleProtein science : a publication of the Protein Society2016
Aggregation of Trp > Glu point mutants of human gamma-D crystallin provides a model for hereditary or UV-induced cataract.
Article in Protein science : a publication of the Protein Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- 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
- Mimicking oxidative damage in γS-crystallin with site-specific incorporation of 5-hydroxytryptophan.Biophysical reports · 2026Article
- Disorder with consequence: Phosphorylation sites in HSPB5 yield distinct structural outcomes.bioRxiv : the preprint server for biology · 2025Article
- Activation mechanism of small heat shock protein HSPB5 revealed by disease-associated mutants.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Eye Lens Protein, γS Crystallin, Undergoes Glutathionylation-Induced Disulfide Bonding Between Cysteines 22 and 26.Biomolecules · 2025Article
- Cataract-prone variants of γD-crystallin populate a conformation with a partially unfolded N-terminal domain under native conditions.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Characterization of βB2-crystallin tryptophan mutants reveals two different folding states in solution.Protein science : a publication of the Protein Society · 2024Article
- Review
- An ultraviolet-driven rescue pathway for oxidative stress to eye lens protein human gamma-D crystallin.Communications chemistry · 2024Article
- Oxidative Stress and Antioxidant-Based Interventional Medicine in Ophthalmology.Pharmaceuticals (Basel, Switzerland) · 2023Review
- The Y46D Mutation Destabilizes Dense Packing of the Second Greek Key Pair of Human γC-Crystallin Causing Congenital Nuclear Cataracts.Biochemistry · 2023Article
- Disordered region encodes α-crystallin chaperone activity toward lens client γD-crystallin.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The mechanism for thermal-enhanced chaperone-like activity of α-crystallin against UV irradiation-induced aggregation of γD-crystallin.Biophysical journal · 2022Article
- Article
- Acquired Disorder and Asymmetry in a Domain-Swapped Model for γ-Crystallin Aggregation.Journal of molecular biology · 2022Article
- Redox chemistry of lens crystallins: A system of cysteines.Experimental eye research · 2021Review
- Chemical Properties Determine Solubility and Stability in βγ-Crystallins of the Eye Lens.Chembiochem : a European journal of chemical biology · 2021Review
- Cumulative deamidations of the major lens protein γS-crystallin increase its aggregation during unfolding and oxidation.Protein science : a publication of the Protein Society · 2020Article
- Human γS-Crystallin-Copper Binding Helps Buffer against Aggregation Caused by Oxidative Damage.Biochemistry · 2020Article
- Two Pathogenic Gene Mutations Identified Associating with Congenital Cataract and Iris Coloboma Respectively in a Chinese Family.Journal of ophthalmology · 2020Article
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6 authors.
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Abstract
Numerous mutations and covalent modifications of the highly abundant, long-lived crystallins of the eye lens cause their aggregation leading to progressive opacification of the lens, cataract. The nature and biochemical mechanisms of the aggregation process are poorly understood, as neither amyloid nor native-state polymers are commonly found in opaque lenses. The βγ-crystallin fold contains four highly conserved buried tryptophans, which can be oxidized to more hydrophilic products, such as kynurenine, upon UV-B irradiation. We mimicked this class of oxidative damage using Trp→Glu point mutants of human γD-crystallin. Such substitutions may represent a model of UV-induced photodamage-introduction of a charged group into the hydrophobic core generating "denaturation from within." The effects of Trp→Glu substitutions were highly position dependent. While each was destabilizing, only the two located in the bottom of the double Greek key fold-W42E and W130E-yielded robust aggregation of partially unfolded intermediates at 37°C and pH 7. The αB-crystallin chaperone suppressed aggregation of W130E, but not W42E, indicating distinct aggregation pathways from damage in the N-terminal vs C-terminal domain. The W130E aggregates had loosely fibrillar morphology, yet were nonamyloid, noncovalent, showed little surface hydrophobicity, and formed at least 20°C below the melting temperature of the native β-sheets. These features are most consistent with domain-swapped polymerization. Aggregation of partially destabilized crystallins under physiological conditions, as occurs in this class of point mutants, could provide a simple in vitro model system for drug discovery and optimization.
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