Structural Biology of Notch Signaling

The conserved Notch signaling pathway plays a central role in development and adult tissue homeostasis. Notch signaling is initiated by binding to a transmembrane ligand. E3 ubiquitin ligase-mediated ligand endocytosis enables release of the negative regulatory region (NRR) of Notch from autoinhibition, which then allows metalloprotease cleavage within the NRR, followed by intramembrane cleavage by the γ-secretase complex. After release from the membrane, the Notch intracellular domain translocates to the nucleus to form a transcriptionally active complex and initiate transcription of Notch-responsive genes. Structural studies of Notch and Notch-associated molecules, which have advanced our understanding of each of these steps in the Notch signaling pathway, are reviewed here.