Structural basis for autoinhibition of Notch

  • A Corrigendum to this article was published on 01 May 2007

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

    References were re-numbered

Notes

  1. 1.

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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.

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Correspondence to Stephen C Blacklow.

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The authors declare no competing financial interests.

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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