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Updated: Jun 3, 2025

Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay

Published on: June 9, 2017

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Genesis and regulation of C-terminal cyclic imides from protein damage

Wenqing Xu1, Zhenguang Zhao1, Matthew Su1

  • 1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.

Proceedings of the National Academy of Sciences of the United States of America
|January 10, 2025
PubMed

Insights

C-terminal cyclic imides are irreversible protein damage modifications. Cellular quality control, involving cereblon (CRBN), removes these aging-related changes, preventing aggregation and maintaining protein stability.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Proteomics

Background:

  • C-terminal cyclic imides are posttranslational modifications resulting from spontaneous intramolecular cleavage of asparagine or glutamine residues.
  • These modifications represent a form of irreversible protein damage that can be recognized and removed by the E3 ligase substrate adapter cereblon (CRBN).
  • Cellular quality control mechanisms, including CRBN, are essential for preventing deleterious effects of these aging-related modifications.

Purpose of the Study:

  • To characterize the primary and secondary structures influencing C-terminal cyclic imide formation in peptides and proteins.
  • To compare C-terminal cyclic imide formation with deamidation, another related protein damage modification.
  • To investigate extrinsic factors, such as solution properties and stressors, that promote C-terminal cyclic imide formation.

Main Methods:

  • Systematic characterization of peptide and protein structures.
  • Comparative analysis of C-terminal cyclic imide formation versus deamidation.
  • Investigation of extrinsic factors affecting protein modification.

Main Results:

  • Identification of specific primary and secondary structures that promote intrinsic C-terminal cyclic imide formation.
  • Demonstration that extrinsic factors and solution properties enhance cyclic imide formation.
  • Observation that CRBN removes protein damage products, preventing aggregation of susceptible proteins like glutathione synthetase.

Conclusions:

  • Insights into the structural determinants of C-terminal cyclic imide formation.
  • Understanding the impact of protein damage on protein stability.
  • Elucidation of the biological role of CRBN in managing protein damage and preventing aggregation.
Keywords:
cereblondeamidationpost-translational modificationprotein aggregationprotein damage

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