ArticleProceedings of the National Academy of Sciences of the United States of America2011
Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 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
- 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
- Ocular delivery of lipid nanoparticles-formulated mRNA encoding lanosterol synthase ameliorates cataract in rats.Nature communications · 2025Article
- Understanding domain swapping in the c-Src SH3 domain through hinge-loop mutagenesis.Acta crystallographica. Section D, Structural biology · 2025Article
- Article
- Identification of Age- and Cataract-Related Changes in High-Density Lens Protein Aggregates.Investigative ophthalmology & visual science · 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
- A scaling relationship between thermodynamic and hydrodynamic interactions in protein solutions.Biophysical journal · 2024Article
- Comparative analysis of thermal adaptations of extremophilic prolyl oligopeptidases.Biophysical journal · 2024Article
- PKM2 aggregation drives metabolism reprograming during aging process.Nature communications · 2024Article
- Characterization of βB2-crystallin tryptophan mutants reveals two different folding states in solution.Protein science : a publication of the Protein Society · 2024Article
- Advanced computational approaches to understand protein aggregation.Biophysics reviews · 2024Review
- Copper binding and protein aggregation: a journey from the brain to the human lens.RSC chemical biology · 2023Article
- The mechanism of self-association of humanJournal of molecular liquids · 2023Article
- Insights to Human γD-Crystallin Unfolding by NMR Spectroscopy and Molecular Dynamics Simulations.International journal of molecular sciences · 2022Article
- Proposed Role for Internal Lens Pressure as an Initiator of Age-Related Lens Protein Aggregation Diseases.Clinical ophthalmology (Auckland, N.Z.) · 2022Article
- Chemical Properties Determine Solubility and Stability in βγ-Crystallins of the Eye Lens.Chembiochem : a European journal of chemical biology · 2021Review
- Function and Aggregation in Structural Eye Lens Crystallins.Accounts of chemical research · 2020Review
- Ultrafast Dynamics of Water-Protein Coupled Motions around the Surface of Eye Crystallin.Journal of the American Chemical Society · 2020Article
2 more citing papers are in PubMed but not listed here.
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Abstract
The prevalent eye disease age-onset cataract is associated with aggregation of human γD-crystallins, one of the longest-lived proteins. Identification of the γ-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native γD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N-terminal domain unfolding. Those strands comprise the domain-domain interface crucial for unusually high stability of γD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135-164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that γD-crystallin may polymerize through successive domain swapping of those three C-terminal β-strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation-prone β-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases.
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