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Structure. 2015 Jul 7;23(7):1227-35. doi: 10.1016/j.str.2015.05.001. Epub 2015 Jun 4.

Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region.

Author information

1
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
3
Department of Radiotherapy (MAASTRO)/GROW - School for Developmental Biology & Oncology, Maastricht University, Maastricht 6229, the Netherlands.
4
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
5
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephen_blacklow@hms.harvard.edu.

Abstract

Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LIN12-Notch repeat (LNR) modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors.

PMID:
26051713
PMCID:
PMC4497832
DOI:
10.1016/j.str.2015.05.001
[Indexed for MEDLINE]
Free PMC Article

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