ArticleThe Journal of biological chemistry2016
An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 77 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
- Human Crystallin Variation and Cataract.Investigative ophthalmology & visual science · 2026Review
- Dimerization of natively folded molecules drives misfolding and aggregation in Cys-depleted variants of cataract-associated human lens γD-crystallin.bioRxiv : the preprint server for biology · 2026Article
- Modeling the Influence of Large Particles on Optical Properties of Nuclear Cataracts: Insights from Enhanced LOCS III-Based Computational Analysis.Diagnostics (Basel, Switzerland) · 2026Article
- Disulfide engineering reveals unexpected pro- and anti-aggregation conformers of human α-synuclein.bioRxiv : the preprint server for biology · 2026Article
- Enzyme-free biochemical production of seamlessly N-to-C cyclized peptides from natural or recombinant proteins.bioRxiv : the preprint server for biology · 2025Article
- Article
- 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
- Enzyme-free biochemical production of seamlessly N-to-C cyclized peptides from natural or recombinant proteins.Methods in enzymology · 2025Article
- Aging of the eye: Lessons from cataracts and age-related macular degeneration.Ageing research reviews · 2024Review
- Review
- MARCH5 promotes STING pathway activation by suppressing polymer formation of oxidized STING.EMBO reports · 2023Article
- Co-translational formation of disulfides guides folding of the SARS-CoV-2 receptor binding domain.Biophysical journal · 2023Article
- Systematic conformation-to-phenotype mapping via limited deep sequencing of proteins.Molecular cell · 2023Article
- Article
- Role of Oxidative Stress in Ocular Diseases: A Balancing Act.Metabolites · 2023Review
- Network Hamiltonian Models for Unstructured Protein Aggregates, with Application to γD-Crystallin.The journal of physical chemistry. B · 2023Article
- Article
- A Single-Molecule Strategy to Capture Non-native Intramolecular and Intermolecular Protein Disulfide Bridges.Nano letters · 2022Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Considerable mechanistic insight has been gained into amyloid aggregation; however, a large number of non-amyloid protein aggregates are considered "amorphous," and in most cases, little is known about their mechanisms. Amorphous aggregation of γ-crystallins in the eye lens causes cataract, a widespread disease of aging. We combined simulations and experiments to study the mechanism of aggregation of two γD-crystallin mutants, W42R and W42Q: the former a congenital cataract mutation, and the latter a mimic of age-related oxidative damage. We found that formation of an internal disulfide was necessary and sufficient for aggregation under physiological conditions. Two-chain all-atom simulations predicted that one non-native disulfide in particular, between Cys(32) and Cys(41), was likely to stabilize an unfolding intermediate prone to intermolecular interactions. Mass spectrometry and mutagenesis experiments confirmed the presence of this bond in the aggregates and its necessity for oxidative aggregation under physiological conditions in vitro Mining the simulation data linked formation of this disulfide to extrusion of the N-terminal β-hairpin and rearrangement of the native β-sheet topology. Specific binding between the extruded hairpin and a distal β-sheet, in an intermolecular chain reaction similar to domain swapping, is the most probable mechanism of aggregate propagation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.