ArticleProtein science : a publication of the Protein Society2010
beta-Strand interactions at the domain interface critical for the stability of human lens gammaD-crystallin.
Article in Protein science : a publication of the Protein Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Characterization of βB2-crystallin tryptophan mutants reveals two different folding states in solution.Protein science : a publication of the Protein Society · 2024Article
- Insight into Pathogenic Mechanism Underlying the Hereditary Cataract Caused by βB2-G149V Mutation.Biomolecules · 2023Article
- Insights to Human γD-Crystallin Unfolding by NMR Spectroscopy and Molecular Dynamics Simulations.International journal of molecular sciences · 2022Article
- βγ-Crystallination Endows a Novel Bacterial Glycoside Hydrolase 64 with CaJournal of bacteriology · 2019Article
- An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin.The Journal of biological chemistry · 2016Article
- The Effect of Attractive Interactions and Macromolecular Crowding on Crystallins Association.PloS one · 2016Article
- The βγ-crystallins: native state stability and pathways to aggregation.Progress in biophysics and molecular biology · 2014Review
- An alternative structural isoform in amyloid-like aggregates formed from thermally denatured human γD-crystallin.Protein science : a publication of the Protein Society · 2014Article
- Comparative analysis of human γD-crystallin aggregation under physiological and low pH conditions.PloS one · 2014Article
- Dissecting the contributions of β-hairpin tyrosine pairs to the folding and stability of long-lived human γD-crystallins.Nanoscale · 2014Article
- Study of the γD-crystallin protein using two-dimensional infrared (2DIR) spectroscopy: experiment and simulation.The journal of physical chemistry. B · 2013Article
- Structural integrity of the Greek key motif in βγ-crystallins is vital for central eye lens transparency.PloS one · 2013Article
- UV-radiation induced disruption of dry-cavities in human γD-crystallin results in decreased stability and faster unfolding.Scientific reports · 2013Article
- Article
- Evolutionary remodeling of βγ-crystallins for domain stability at cost of Ca2+ binding.The Journal of biological chemistry · 2011Article
- Inhibition of unfolding and aggregation of lens protein human gamma D crystallin by sodium citrate.Experimental eye research · 2011Article
- Increased hydrophobicity and decreased backbone flexibility explain the lower solubility of a cataract-linked mutant of γD-crystallin.Journal of molecular biology · 2011Article
- Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Contributions of aromatic pairs to the folding and stability of long-lived human γD-crystallin.Protein science : a publication of the Protein Society · 2011Article
- The group II chaperonin Mm-Cpn binds and refolds human γD crystallin.Protein science : a publication of the Protein Society · 2011Article
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Abstract
Human age-onset cataracts are believed to be caused by the aggregation of partially unfolded or covalently damaged lens crystallin proteins; however, the exact molecular mechanism remains largely unknown. We have used microseconds of molecular dynamics simulations with explicit solvent to investigate the unfolding process of human lens gammaD-crystallin protein and its isolated domains. A partially unfolded folding intermediate of gammaD-crystallin is detected in simulations with its C-terminal domain (C-td) folded and N-terminal domain (N-td) unstructured, in excellent agreement with biochemical experiments. Our simulations strongly indicate that the stability and the folding mechanism of the N-td are regulated by the interdomain interactions, consistent with experimental observations. A hydrophobic folding core was identified within the C-td that is comprised of a and b strands from the Greek key motif 4, the one near the domain interface. Detailed analyses reveal a surprising non-native surface salt-bridge between Glu135 and Arg142 located at the end of the ab folded hairpin turn playing a critical role in stabilizing the folding core. On the other hand, an in silico single E135A substitution that disrupts this non-native Glu135-Arg142 salt-bridge causes significant destabilization to the folding core of the isolated C-td, which, in turn, induces unfolding of the N-td interface. These findings indicate that certain highly conserved charged residues, that is, Glu135 and Arg142, of gammaD-crystallin are crucial for stabilizing its hydrophobic domain interface in native conformation, and disruption of charges on the gammaD-crystallin surface might lead to unfolding and subsequent aggregation.
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