ArticleAging cell2014
Human protein aging: modification and crosslinking through dehydroalanine and dehydrobutyrine intermediates.
Article in Aging cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed.
- Self-assembly of dental surface nanofilaments and remineralisation by SnFScientific reports · 2019Trial
- Deamidation Promotes AGE-Modifications in Human Lens γS-Crystallin.Biochemistry · 2026Article
- Loss of LanC-like proteins delays post-injury regeneration of aging skeletal muscles.bioRxiv : the preprint server for biology · 2026Article
- Lens aging and disease: Molecular mechanisms, functional consequences, and pharmacological implications.Progress in retinal and eye research · 2026Review
- Genesis and regulation of C-terminal cyclic imides from protein damage.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dehydroamino acids and their crosslinks in Alzheimer's disease aggregates.Brain communications · 2025Article
- Thiol-Mediated Enhancement of NACS chemical biology · 2024Article
- The Brain and Spinal Microvasculature in Normal Aging.The journals of gerontology. Series A, Biological sciences and medical sciences · 2023Review
- Emerging roles of low-molecular-weight thiols at the host-microbe interface.Current opinion in chemical biology · 2023Review
- Selenium in Peptide Chemistry.Molecules (Basel, Switzerland) · 2023Review
- Dehydroalanine and dehydrobutyrine in aging and cataractous lenses reveal site-specific consequences of spontaneous protein degradation.Frontiers in ophthalmology · 2023Article
- Emerging chemistry and biology in protein glutathionylation.Current opinion in chemical biology · 2022Review
- Defining the S-Glutathionylation Proteome by Biochemical and Mass Spectrometric Approaches.Antioxidants (Basel, Switzerland) · 2022Review
- Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens.The Journal of biological chemistry · 2022Review
- In the Chalcogenoxide Elimination Panorama: Systematic Insight into a Key Reaction.The Journal of organic chemistry · 2022Article
- Discovery of Dehydroamino Acid Residues in the Capsid and Matrix Structural Proteins of HIV-1.Journal of proteome research · 2022Article
- Lens Aquaporins in Health and Disease: Location is Everything!Frontiers in physiology · 2022Review
- Oxidative Crosslinking of Peptides and Proteins: Mechanisms of Formation, Detection, Characterization and Quantification.Molecules (Basel, Switzerland) · 2021Review
- Spontaneous Cleavage at Glu and Gln Residues in Long-Lived Proteins.ACS chemical biology · 2021Article
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4 authors.
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Abstract
Nonenzymatic post-translational modification (PTM) of proteins is a fundamental molecular process of aging. The combination of various modifications and their accumulation with age not only affects function, but leads to crosslinking and protein aggregation. In this study, aged human lens proteins were examined using HPLC-tandem mass spectrometry and a blind PTM search strategy. Multiple thioether modifications of Ser and Thr residues by glutathione (GSH) and its metabolites were unambiguously identified. Thirty-four of 36 sites identified on 15 proteins were found on known phosphorylation sites, supporting a mechanism involving dehydroalanine (DHA) and dehydrobutyrine (DHB) formation through β-elimination of phosphoric acid from phosphoserine and phosphothreonine with subsequent nucleophilic attack by GSH. In vitro incubations of phosphopeptides demonstrated that this process can occur spontaneously under physiological conditions. Evidence that this mechanism can also lead to protein-protein crosslinks within cells is provided where five crosslinked peptides were detected in a human cataractous lens. Nondisulfide crosslinks were identified for the first time in lens tissue between βB2- & βB2-, βA4- & βA3-, γS- & βB1-, and βA4- & βA4-crystallins and provide detailed structural information on in vivo crystallin complexes. These data suggest that phosphoserine and phosphothreonine residues represent susceptible sites for spontaneous breakdown in long-lived proteins and that DHA- and DHB-mediated protein crosslinking may be the source of the long-sought after nondisulfide protein aggregates believed to scatter light in cataractous lenses. Furthermore, this mechanism may be a common aging process that occurs in long-lived proteins of other tissues leading to protein aggregation diseases.
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