Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

PROTEIN DEGRADATION

Understanding the Pro/N-end rule pathway

Nature Chemical Biology volume 14, pages 415–416 (2018)Cite this article

Regulated destruction of proteins underlies just about everything a cell does. A structural study of human Gid4, the N-recognin of the Pro/N-end rule pathway that targets proteins through their N-terminal proline, illuminates the recognition of substrates by this proteolytic system.

The lifespans of protein molecules in a cell range from less than a minute to many days. Selective destruction of intracellular proteins protects cells from misfolded or otherwise abnormal proteins and controls the levels of many regulatory proteins that have evolved to be short-lived. A major part of regulated protein degradation is mediated by the ubiquitin (Ub)-proteasome system (UPS)1,2. The UPS comprises a set of pathways that have in common two kinds of enzymes: (i) a Ub ligase, which recognizes a protein substrate through its degradation signal (degron) and covalently conjugates Ub (usually in the form of a poly-Ub chain) to the targeted protein; (ii) an ATP-dependent, multisubunit protease called the 26S proteasome, which recognizes a polyubiquitylated protein substrate and unfolds it while processively destroying it to short (~10-residue) peptides1,2. A glimpse of UPS complexity can be conveyed by the fact that a mammalian genome encodes nearly 1,000 distinct Ub ligases.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1: Structural basis of N-degron recognition.

References

  1. Varshavsky, A. Trends Biochem. Sci. 30, 283–286 (2005).

    Article  CAS  Google Scholar 

  2. Finley, D., Ulrich, H. D., Sommer, T. & Kaiser, P. Genetics 192, 319–360 (2012).

    Article  CAS  Google Scholar 

  3. Bachmair, A., Finley, D. & Varshavsky, A. Science 234, 179–186 (1986).

    Article  CAS  Google Scholar 

  4. Hwang, C. S., Shemorry, A. & Varshavsky, A. Science 327, 973–977 (2010).

    Article  CAS  Google Scholar 

  5. Chen, S. J., Wu, X., Wadas, B., Oh, J.-H. & Varshavsky, A. Science 355, eaal3655 (2017).

    Article  Google Scholar 

  6. Varshavsky, A. Protein Sci. 20, 1298–1345 (2011).

    Article  CAS  Google Scholar 

  7. Dougan, D. A., Micevski, D. & Truscott, K. N. Biochim. Biophys. Acta 1823, 83–91 (2012).

    Article  CAS  Google Scholar 

  8. Tasaki, T., Sriram, S. M., Park, K. S. & Kwon, Y. T. Annu. Rev. Biochem. 81, 261–289 (2012).

    Article  CAS  Google Scholar 

  9. Gibbs, D. J., Bacardit, J., Bachmair, A. & Holdsworth, M. J. Trends Cell Biol 24, 603–611 (2014).

    Article  CAS  Google Scholar 

  10. Cha-Molstad, H. et al. Nat. Commun. 8, 102 (2017).

    Article  Google Scholar 

  11. Menssen, R. et al. J. Biol. Chem. 287, 25602–25614 (2012).

    Article  CAS  Google Scholar 

  12. Alibhoy, A. A. & Chiang, H. L. World J. Biol. Chem. 2, 239–245 (2011).

    Article  Google Scholar 

  13. Dong, C. et al. Nat. Chem. Biol. https://doi.org/10.1038/s41589-018-0036-1 (2018).

Download references

Author information

Authors and Affiliations

  1. La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia

    David A. Dougan

  2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Alexander Varshavsky

Authors
  1. David A. Dougan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Varshavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to David A. Dougan or Alexander Varshavsky.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dougan, D.A., Varshavsky, A. Understanding the Pro/N-end rule pathway. Nat Chem Biol 14, 415–416 (2018). https://doi.org/10.1038/s41589-018-0045-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-018-0045-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing