Spontaneous protein–protein crosslinking at glutamine and glutamic acid residues in long-lived proteins
Publication Name
Biochemical Journal
Abstract
Long-lived proteins (LLPs) are susceptible to the accumulation of both enzymatic and spontaneous post-translational modifications (PTMs). A prominent PTM observed in LLPs is covalent protein–protein crosslinking. In this study, we examined aged human lenses and found several proteins to be crosslinked at Glu and Gln residues. This new covalent bond involves the amino group of Lys or an α-amino group. A number of these crosslinks were found in intermediate filament proteins. Such crosslinks could be reproduced experimentally by incubation of Glu- or Gln-containing peptides and their formation was consistent with an amino group attacking a glutarimide intermediate. These findings show that both Gln and Glu residues can act as sites for spontaneous covalent crosslinking in LLPs and they provide a mechanistic explanation for an otherwise puzzling observation, that a major fraction of Aβ in the human brain is crosslinked via Glu 22 and the N-terminal amino group.
Open Access Status
This publication may be available as open access
Volume
478
Issue
2
First Page
327
Last Page
339
Funding Number
P30 EY008126
Funding Sponsor
National Institutes of Health