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.
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January 2021
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High protein levels of protein kinase C confer a survival advantage in many cancers, including pancreatic cancer. In this issue, Tovell and Newton (pp. 341–355) review the mechanisms controlling the stability of protein kinase C, focusing on negative regulation by the phosphatase PHLPP as a potential strategy to restore protein levels of the kinase. Image provided by Hannah Tovell and was created with BioRender.com.
Research Article|
January 22 2021
Spontaneous protein–protein crosslinking at glutamine and glutamic acid residues in long-lived proteins
Michael G. Friedrich
;
Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
1Illawarra Health and Medical Research Institute, and Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
Correspondence: Michael G. Friedrich (michaelf@uow.edu.au)
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Zhen Wang;
Zhen Wang
Data curation, Software, Formal analysis, Investigation, Methodology, Writing - review & editing
2Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, U.S.A.
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Kevin L. Schey;
Kevin L. Schey
Supervision, Writing - review & editing
2Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN, U.S.A.
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Roger J. W. Truscott
Roger J. W. Truscott
1Illawarra Health and Medical Research Institute, and Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia
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Publisher: Portland Press Ltd
Received:
October 18 2020
Revision Received:
December 15 2020
Accepted:
December 18 2020
Accepted Manuscript online:
December 21 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (2): 327–339.
Article history
Received:
October 18 2020
Revision Received:
December 15 2020
Accepted:
December 18 2020
Accepted Manuscript online:
December 21 2020
Citation
Michael G. Friedrich, Zhen Wang, Kevin L. Schey, Roger J. W. Truscott; Spontaneous protein–protein crosslinking at glutamine and glutamic acid residues in long-lived proteins. Biochem J 29 January 2021; 478 (2): 327–339. doi: https://doi.org/10.1042/BCJ20200798
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