Cleavage C-terminal to Asp leads to covalent crosslinking of long-lived human proteins.
Aging
Cataract
Lens
Long-lived proteins
Racemisation
Journal
Biochimica et biophysica acta. Proteins and proteomics
ISSN: 1878-1454
Titre abrégé: Biochim Biophys Acta Proteins Proteom
Pays: Netherlands
ID NLM: 101731734
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
18
02
2019
revised:
29
05
2019
accepted:
16
06
2019
pubmed:
22
6
2019
medline:
27
11
2019
entrez:
22
6
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31226490
pii: S1570-9639(19)30114-1
doi: 10.1016/j.bbapap.2019.06.009
pmc: PMC9227964
mid: NIHMS1813041
pii:
doi:
Substances chimiques
Aquaporins
0
Eye Proteins
0
Peptides
0
alpha-Crystallin A Chain
0
alpha-Crystallin B Chain
0
aquaporin 0
0
Aspartic Acid
30KYC7MIAI
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
831-839Subventions
Organisme : NEI NIH HHS
ID : P30 EY008126
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY024258
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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