title: Structural basis for autoinhibition of Notch.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Gordon
authors.forename: Didem
authors.initials: D
authors.lastname: Vardar-Ulu
authors.forename: Gavin
authors.initials: G
authors.lastname: Histen
authors.forename: Cheryll
authors.initials: C
authors.lastname: Sanchez-Irizarry
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
mesh_terms: 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
chemical_list: D051883:Receptor, Notch2