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Structural basis for autoinhibition of Notch

Nature Structural & Molecular Biology volume 14, pages 295–300 (2007)Cite this article

A Corrigendum to this article was published on 01 May 2007

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Abstract

Notch receptors transmit signals between adjacent cells. Signaling is initiated when ligand binding induces metalloprotease cleavage of Notch within an extracellular negative regulatory region (NRR). We present here the X-ray structure of the human NOTCH2 NRR, which adopts an autoinhibited conformation. Extensive interdomain interactions within the NRR bury the metalloprotease site, showing that a substantial conformational movement is necessary to expose this site during activation by ligand. Leukemia-associated mutations in NOTCH1 probably release autoinhibition by destabilizing the conserved hydrophobic core of the NRR.

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Figure 1: Notch domain organization and overall views of the structure.
Figure 2: Interface between the LNR and HD domains.
Figure 3: Cell-based reporter gene assays showing that stepwise removal of LNR domain elements causes ligand-independent activation of NOTCH.

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  • 01 April 2007

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Notes

  1. *NOTE: In the version of this article initially published, three references were missing from the reference list. The corrected reference appears above and references have been renumbered accordingly. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank Mike Eck and Angela Toms for crystallographic suggestions and Kelly Arnett and Mike Malecki for critical reading of the manuscript. This work was supported by American Cancer Society Postdoctoral Fellowships (WRG and DVU), a Leukemia and Lymphoma Society Fellowship (WRG), and NIH grants to SCB and JCA.

Author information

Author notes

  1. Didem Vardar-Ulu

    Present address: Present address: Department of Chemistry, Wellesley College, 106 Central Street, Wellesley, Massachusetts 02481, USA.,

  2. Wendy R Gordon and Didem Vardar-Ulu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, 02115, Massachusetts, USA

    Wendy R Gordon, Didem Vardar-Ulu, Gavin Histen, Cheryll Sanchez-Irizarry, Jon C Aster & Stephen C Blacklow

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  1. Wendy R Gordon
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Corresponding author

Correspondence to Stephen C Blacklow.

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Supplementary information

Supplementary Fig. 1

Sequence alignment of the NRR region of various Notch receptors (PDF 2309 kb)

Supplementary Fig. 2

Representative electron density (PDF 370 kb)

Supplementary Fig. 3

Comparison of human NOTCH2 HD domain with SEA domains from mucins (PDF 175 kb)

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Gordon, W., Vardar-Ulu, D., Histen, G. et al. Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 14, 295–300 (2007). https://doi.org/10.1038/nsmb1227

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