Structural basis for autoinhibition of Notch

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

Research output: Contribution to journalArticlepeer-review

232 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)295-300
Number of pages6
JournalNature Structural and Molecular Biology
Volume14
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

Bibliographical note

Funding Information:
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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