ArticleJournal of molecular biology2011
Characterization of a transient unfolding intermediate in a core mutant of γS-crystallin.
Article in Journal of molecular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 34 citations in OpenAlex.
- Candidate Genes for Non-Syndromic Pediatric Cataracts.Clinical ophthalmology (Auckland, N.Z.) · 2026Review
- Characterization of βB2-crystallin tryptophan mutants reveals two different folding states in solution.Protein science : a publication of the Protein Society · 2024Article
- Acquired Disorder and Asymmetry in a Domain-Swapped Model for γ-Crystallin Aggregation.Journal of molecular biology · 2022Article
- Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract.Scientific reports · 2021Article
- Aggregation pathways of human γ D crystallin induced by metal ions revealed by time dependent methods.PeerJ · 2020Article
- Altered Protein Dynamics and Increased Aggregation of Human γS-Crystallin Due to Cataract-Associated Deamidations.Biochemistry · 2019Article
- An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin.The Journal of biological chemistry · 2016Article
- Aggregation of Trp > Glu point mutants of human gamma-D crystallin provides a model for hereditary or UV-induced cataract.Protein science : a publication of the Protein Society · 2016Article
- Wild-type human γD-crystallin promotes aggregation of its oxidation-mimicking, misfolding-prone W42Q mutant.The Journal of biological chemistry · 2015Article
- The βγ-crystallins: native state stability and pathways to aggregation.Progress in biophysics and molecular biology · 2014Review
- Solution properties of γ-crystallins: compact structure and low frictional ratio are conserved properties of diverse γ-crystallins.Protein science : a publication of the Protein Society · 2014Article
- NMR paves the way for atomic level descriptions of sparsely populated, transiently formed biomolecular conformers.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Structure and dynamics of the fish eye lens protein, γM7-crystallin.Biochemistry · 2013Article
- The human W42R γD-crystallin mutant structure provides a link between congenital and age-related cataracts.The Journal of biological chemistry · 2013Article
- A role for γS-crystallin in the organization of actin and fiber cell maturation in the mouse lens.The FEBS journal · 2012Article
- ¹H, ¹³C, and ¹⁵N assignments of wild-type human γS-crystallin and its cataract-related variant γS-G18V.Biomolecular NMR assignments · 2012Article
- The mutation V42M distorts the compact packing of the human gamma-S-crystallin molecule, resulting in congenital cataract.PloS one · 2012Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
In many age-related and neurological diseases, formerly native proteins aggregate via formation of a partially unfolded intermediate. γS-Crystallin is a highly stable structural protein of the eye lens. In the mouse Opj cataract, a non-conservative F9S mutation in the N-terminal domain core of γS allows the adoption of a native fold but renders the protein susceptible to temperature- and concentration-dependent aggregation, including fibril formation. Hydrogen/deuterium exchange and denaturant unfolding studies of this mutant protein (Opj) have suggested the existence of a partially unfolded intermediate in its aggregation pathway. Here, we used NMR and fluorescence spectroscopy to obtain evidence for this intermediate. In 3.5 M urea, Opj forms a stable and partially unfolded entity that is characterized by an unstructured N-terminal domain and a largely intact C-terminal domain. Under physiologically relevant conditions, Carr-Purcell-Meiboom-Gill T(2)-relaxation dispersion experiments showed that the N-terminal domain residues were in conformational exchange with a loosely structured intermediate with a population of 1-2%, which increased with temperature. This provides direct evidence for a model in which proteins of native fold can explore an intermediate state with an increased propensity for formation of aggregates, such as fibrils. For the crystallins, this shows how inherited sequence variants or environmentally induced modifications can destabilize a well-folded protein, allowing the formation of intermediates able to act as nucleation sites for aggregation and the accumulation of light-scattering centers in the cataractous lens.
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