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Nucleosomal association and altered interactome underlie the mechanism of cataract caused by the R54C mutation of αA-crystallin
Open accessPublished version of a preprint
Abstract
Background αA-crystallin plays an important role in eye lens development. Its N-terminal domain is implicated in several important biological functions. Mutations in certain conserved arginine residues in the N-terminal region of αA-crystallin lead to cataract with characteristic cytoplasmic/nuclear aggregation of the mutant protein. In this study, we attempt to gain mechanistic insights into the congenital cataract caused by the R54C mutation in human αA-crystallin. Methods We used several spectroscopic techniques to investigate the structure and function of the wild-type and R54CαA-crystallin. Immunoprecipitation, chromatin-enrichment followed by western blotting, immunofluorescence and cell-viability assay were performed to study the interaction partners, chromatin-association, stress-like response and cell-death caused by the mutant. Results Although R54CαA-crystallin exhibited slight changes in quaternary structure, its chaperone-like activity was comparable to that of wild-type. When expressed in lens epithelial cells, R54CαA-crystallin exhibited a speckled appearance in the nucleus rather than cytoplasmic localization. R54CαA-crystallin triggered a stress-like response, resulting in nuclear translocation of αB-crystallin, disassembly of cytoskeletal elements and activation of caspase 3, leading to apoptosis. Analysis of the "interactome" revealed an increase in interaction of the mutant protein with nucleosomal histones, and its association with chromatin. Conclusions The study shows that alteration of "interactome" and nucleosomal association, rather than loss of chaperone-like activity, is the molecular basis of cataract caused by the R54C mutation in αA-crystallin. General significance The study provides a novel mechanism of cataract caused by a mutant of αA-crystallin, and sheds light on the possible mechanism of stress and cell death caused by such nuclear inclusions.
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Metadata
- Authors
- Ahsan, S. M., Bakthisaran, R., Tangirala, R., & Rao, C. M.
- Affiliations
- Centre for Cellular and Molecular Biology (IN)
- Corresponding author
- Rao, Ch. Mohan
- ORCID
- Rao, Ch. Mohan
- Venue
- Biochimica et Biophysica Acta (BBA) - General Subjects
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 1865
- Issue
- 5
- Pages
- 129846
- ISSN
- 0304-4165 (ISSN-L)
- OpenAlex
- W3118249802
- Cited by
- 6
- References
- 77
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2
- FWCI
- 0.31
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- alphaA-crystallin, congenital cataract, protein-protein interaction network, chromatin association, histone interaction, chaperone-like activity, lens epithelial cells, nuclear translocation, alphaB-crystallin, caspase-3 activation, apoptosis, stress response, intranuclear inclusions
- MeSH terms
- Cataract, Cell Line, Crystallins, Humans, Lens, Crystalline, Nucleosomes, Point Mutation, Protein Interaction Maps
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