Article | Published:

Defining the geometry of the two-component proteasome degron

Nature Chemical Biology volume 7, pages 161167 (2011) | Download Citation

Abstract

The eukaryotic 26S proteasome controls cellular processes by degrading specific regulatory proteins. Most proteins are targeted for degradation by a signal or degron that consists of two parts: a proteasome-binding tag, typically covalently attached polyubiquitin chains, and an unstructured region that serves as the initiation region for proteasomal proteolysis. Here we have characterized how the arrangement of the two degron parts in a protein affects degradation. We found that a substrate is degraded efficiently only when its initiation region is of a certain minimal length and is appropriately separated in space from the proteasome-binding tag. Regions that are located too close or too far from the proteasome-binding tag cannot access the proteasome and induce degradation. These spacing requirements are different for a polyubiquitin chain and a ubiquitin-like domain. Thus, the arrangement and location of the proteasome initiation region affect a protein's fate and are important in selecting proteins for proteasome-mediated degradation.

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Acknowledgements

We thank S. Elsasser (Harvard University Medical School), D. Finley (Harvard University Medical School), B.S. Glick (University of Chicago) and Y. Saeki (Tokyo Metropolitan Institute of Medical Science) for providing plasmids and yeast strains and members of the Matouschek lab for advice and comments. The authors greatly appreciate and gratefully acknowledge N. Nukina (RIKEN) for his support and the use of his laboratory equipment. We also thank G. Leigh for editing the manuscript. The work was supported by grants R01GM063004 and U54CA143869 from the US National Institutes of Health, by Ministry of Education, Culture, Sports, Science and Technology of Japan Grant-in-Aid 22770137 (T.I.) and by the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. T.I. also gratefully acknowledges a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and the RIKEN Special Postdoctoral Researchers Program.

Author information

Affiliations

  1. Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.

    • Tomonao Inobe
    • , Susan Fishbain
    • , Sumit Prakash
    •  & Andreas Matouschek
  2. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.

    • Tomonao Inobe
    • , Susan Fishbain
    • , Sumit Prakash
    •  & Andreas Matouschek
  3. Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama, Japan.

    • Tomonao Inobe

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Contributions

T.I., S.F., S.P. and A.M. designed and interpreted the experiments and wrote the manuscript. T.I., S.F. and S.P. performed the experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andreas Matouschek.

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DOI

https://doi.org/10.1038/nchembio.521

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