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A conserved processing mechanism regulates the activity of transcription factors Cubitus interruptus and NF-κB

Nature Structural & Molecular Biology volume 12, pages 10451053 (2005) | Download Citation

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Abstract

The proteasome degrades some proteins, such as transcription factors Cubitus interruptus (Ci) and NF-κB, to generate biologically active protein fragments. Here we have identified and characterized the signals in the substrate proteins that cause this processing. The minimum signal consists of a simple sequence preceding a tightly folded domain in the direction of proteasome movement. The strength of the processing signal depends primarily on the complexity of the simple sequence rather than on amino acid identity, the resistance of the folded domain to unraveling by the proteasome and the spacing between the simple sequence and folded domain. We show that two unrelated transcription factors, Ci and NF-κB, use this mechanism to undergo partial degradation by the proteasome in vivo. These findings suggest that the mechanism is conserved evolutionarily and that processing signals may be widespread in regulatory proteins.

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Acknowledgements

This work is dedicated to Irving M. Klotz. We thank R.W. Carthew and M. Feller for help and advice with the Ci cell culture experiments and C. Horvath and J.-P. Parisien for help with the NF-κB cell culture experiments. We also thank J. Widom, R.W. Carthew, C. Horvath, S. Prakash and S. Fishbain for advice. We are grateful to N. Shah and C. Malalis for constructing several plasmids. The work was supported by grant GM063004 from the US National Institutes of Health.

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  1. Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208, USA and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.

    • Lin Tian
    • , Robert A Holmgren
    •  & Andreas Matouschek

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The authors declare no competing financial interests.

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Correspondence to Andreas Matouschek.

Supplementary information

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  1. 1.

    Supplementary Fig. 1

    Degradation depends on ubiquitin proteasome pathway.

  2. 2.

    Supplementary Fig. 2

    Gel filtration.

  3. 3.

    Supplementary Fig. 3

    Spacing requirement.

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https://doi.org/10.1038/nsmb1018

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