Abstract
Ubiquitin-dependent protein degradation regulates myriad fundamental cellular processes. At its core are degradation signals, or degrons, that initiate substrate engagement and ubiquitination by E3 ubiquitin ligases. Here we highlight how a variety of degradation signals promote substrate–E3 ligase interactions to orchestrate protein turnover with precision. While short linear motifs are frequently identified as degrons, an increasing number of degrons have recently been mapped to high-order protein structures, underscoring the architectural diversity and cryptic nature of degradation signals. Furthermore, nonproteinaceous signals beyond degrons often facilitate the precise control of protein ubiquitination. These additional signals can reside within substrates and E3 ligases or at their interfaces. Finally, we discuss how dysregulation of degrons and degradation signals is linked to human diseases. A deeper mechanistic understanding of degradation signals will guide new therapeutic strategies, whether by restoring defective protein ubiquitination or by harnessing targeted protein degradation.
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Acknowledgements
B.W. and N.Z. are supported by the Howard Hughes Medical Institute, the Washington Research Foundation and funds from the US National Institutes of Health (R01 HD097408, R01 DA056370 and R01HL112808). N.Z. is a Howard Hughes Medical Institute Investigator.
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B.W. and N.Z. conceived the central themes of the Review. B.W. wrote the initial draft. N.Z. made the figures. B.W. and N.Z. completed the final preparation.
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N.Z. is one of the scientific cofounders and a shareholder of SEED Therapeutics, and serves as a member of the scientific advisory boards of SyntheX, Molecular Glue Labs, Cold Start Therapeutics and Differentiated Therapeutics, with financial interests. B.W. declares no competing interests.
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Structurally characterized human E3–degron complexes.
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Wang, B., Zheng, N. Degrons and degradation signals beyond short linear motifs. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-02056-2
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DOI: https://doi.org/10.1038/s41589-025-02056-2
