ArticleBiochimica et biophysica acta. Proteins and proteomics2019
Cleavage C-terminal to Asp leads to covalent crosslinking of long-lived human proteins.
Article in Biochimica et biophysica acta. Proteins and proteomics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Ribosome Molecular Aging Shapes Translation Dynamics.bioRxiv : the preprint server for biology · 2026Article
- Methods for studying mammalian aquaporin biology.Biology methods & protocols · 2023Review
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- Insight into the Mammalian Aquaporin Interactome.International journal of molecular sciences · 2022Review
- Lens Aquaporins in Health and Disease: Location is Everything!Frontiers in physiology · 2022Review
- Spontaneous Cleavage at Glu and Gln Residues in Long-Lived Proteins.ACS chemical biology · 2021Article
- Article
- Acceleration of age-induced proteolysis in the guinea pig lens nucleus by in vivo exposure to hyperbaric oxygen: A mass spectrometry analysis.Experimental eye research · 2021Article
- New insights into the mechanisms of age-related protein-protein crosslinking in the human lens.Experimental eye research · 2021Review
- Chemical Properties Determine Solubility and Stability in βγ-Crystallins of the Eye Lens.Chembiochem : a European journal of chemical biology · 2021Review
- Tau Is Truncated in Five Regions of the Normal Adult Human Brain.International journal of molecular sciences · 2021Article
- Proteomic characterization of the human lens and Cataractogenesis.Expert review of proteomics · 2021Review
- Spontaneous protein-protein crosslinking at glutamine and glutamic acid residues in long-lived proteins.The Biochemical journal · 2021Article
- Detecting aspartate isomerization and backbone cleavage after aspartate in intact proteins by NMR spectroscopy.Journal of biomolecular NMR · 2021Article
- Molecular signature for senile and complicated cataracts derived from analysis of sumoylation enzymes and their substrates in human cataract lenses.Aging cell · 2020Article
- Spatiotemporal changes in the human lens proteome: Critical insights into long-lived proteins.Progress in retinal and eye research · 2020Review
- Mechanism of protein cleavage at asparagine leading to protein-protein cross-links.The Biochemical journal · 2019Article
- Molecular Processes Implicated in Human Age-Related Nuclear Cataract.Investigative ophthalmology & visual science · 2019Review
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
With age, long-lived proteins in the human body deteriorate, which can have consequences both for aging and disease. The aging process is often associated with the formation of covalently crosslinked proteins. Currently our knowledge of the mechanism of formation of these crosslinks is limited. In this study, proteomics was used to characterize sites of covalent protein-protein crosslinking and identify a novel mechanism of protein-protein crosslinking in the adult human lens. In this mechanism, Lys residues are crosslinked to C-terminal Asp residues that are formed by non-enzymatic protein truncation. Ten different crosslinks were identified in major lens proteins such as αA-crystallin, αB-crystallin and AQP0. Crosslinking in AQP0 increased significantly with age and also increased significantly in cataract lenses compared with normal lenses. Using model peptides, a mechanism of formation of the Lys-Asp crosslink was elucidated. The mechanism involves spontaneous peptide cleavage on the C-terminal side of Asp residues which can take place in the pH range 5-7.4. Cleavage appears to involve attack by the side chain carboxyl group on the adjacent peptide bond, resulting in the formation of a C-terminal Asp anhydride. This anhydride intermediate can then either react with water to form Asp, or with a nucleophile, such as a free amine group to form a crosslink. If an ε-amino group of Lys or an N-terminal amine group attacks the anhydride, a covalent protein-protein crosslink will be formed. This bi-phasic mechanism represents the first report to link two spontaneous events: protein cleavage and crosslinking that are characteristic of long-lived proteins.
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