Structural basis for autoinhibition of Notch.
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.
Gordon
Wendy R
WR
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA.
Vardar-Ulu
Didem
D
Histen
Gavin
G
Sanchez-Irizarry
Cheryll
C
Aster
Jon C
JC
Blacklow
Stephen C
SC
D018360:Crystallography, X-Ray; D017930:Genes, Reporter; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051883:Receptor, Notch2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
D051883:Receptor, Notch2