Title

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

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Link to publisher version (DOI)

http://dx.doi.org/10.1042/BCJ20200798