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Post-translational modifications

C-degron mimicry confers E3 ligase selectivity

Nature Reviews Molecular Cell Biology volume 24, page 241 (2023)Cite this article

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E3 ubiquitin ligases are a part of the ubiquitin–proteasome system and act by transferring ubiquitin to substrate proteins, ultimately leading to their degradation. A subset of E3 ubiquitin ligases, termed ‘C-degron’ E3 ligases, recruit substrate proteins by recognition of C-terminal destabilizing motifs (C-degrons). These sequences are also found in other proteins, including ubiquitin and ubiquitin-like (UBL) proteins, that are not targeted for ubiquitylation, raising the question of how E3 ligases discriminate these from bona fide substrates. Scott et al. now show that C-degron mimicry by the C-terminus of the human E3 ligase CRL2KLHDC2 results in autoinhibition of the enzyme and promotes substrate selectivity.

Competitive binding and ubiquitylation assays confirmed that while NEDD8 can indeed bind to the substrate-binding domain (SBD) of KLHDC2, it does not become ubiquitylated by CRL2KLHDC2, indicating that binding to the E3 ligase is not sufficient for ubiquitin transfer.

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  1. Nature Reviews Molecular Cell Biology http://www.nature.com/nrm/

    Lisa Heinke

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  1. Lisa Heinke
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Correspondence to Lisa Heinke.

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Heinke, L. C-degron mimicry confers E3 ligase selectivity. Nat Rev Mol Cell Biol 24, 241 (2023). https://doi.org/10.1038/s41580-023-00597-9

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