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Autoregulation of an E2 enzyme by ubiquitin-chain assembly on its catalytic residue

Nature Cell Biology volume 9, pages 422427 (2007) | Download Citation

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Abstract

Cells have quality-control mechanisms to recognize non-native protein structures and either help the proteins fold or promote their degradation1,2. Ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) work together to assemble polyubiquitin chains on misfolded or misassembled proteins, which are then degraded by the proteasome3,4. Here, we find that Ubc7, a yeast E2, can itself undergo degradation when its levels exceed that of its binding partner Cue1, a transmembrane protein that tethers Ubc7 to the endoplasmic reticulum5,6. Unassembled, and thus mislocalized, Ubc7 is targeted to the proteasome by Ufd4, a homologous to E6-AP C-terminus (HECT)-class E3. Ubc7 is autoubiquitinated by a novel mechanism wherein the catalytic cysteine, instead of a lysine residue, provides the polyubiquitin chain acceptor site, and this cysteine-linked chain functions as a degradation signal. The polyubiquitin chain can also be transferred to a lysine side chain, suggesting a mechanism for polyubiquitin chain assembly that precedes substrate modification.

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Acknowledgements

We thank: Y. Reiss, G. Jona and O. Kerscher for valuable discussions; Y. Xie for providing the yeast deletion strain plate; Y. Xie, R. Hampton and T. Sommer for plasmids; and T. Biederer, R. Felberbaum, G. Jona and S. Kreft for comments on the manuscript. This work was supported by a U.S. National Institutes of Health (NIH) grant (GM046904) to M.H.

Author information

Affiliations

  1. Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.

    • Tommer Ravid
    •  & Mark Hochstrasser

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Contributions

T.R. performed all the experiments, and T.R. and M.H. conceived and designed the experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mark Hochstrasser.

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    Supplementary Information

    Supplementary Figures S1, S2, S3, S4, Supplementary Table and Methods

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DOI

https://doi.org/10.1038/ncb1558

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