Fringe benefits: Functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors

The Notch family of receptors plays essential roles in many phases of development, and dysregulation of Notch activity is increasingly recognized as a player in many diseases. O-Glycosylation of the Notch extracellular domain is essential for Notch activity, and tissue-specific alterations in the glycan structures are known to regulate activity. Here we review recent advances in identification and characterization of the enzymes responsible for glycosylating Notch and molecular mechanisms for how these O-glycans affect Notch activity.

► Notch is modified at multiple sites with O-fucose and O-glucose glycans ► Elongation of O-fucose glycans by Fringe regulates Notch-ligand binding. ► Rumi encodes the protein O-glucosyltransferase responsible for modifying Notch. ► O-Glucose may stabilize Notch to allow proper receptor activation. ► Multiple O-glycan sites contribute to Notch-ligand binding and activity ► O-Glycosylation may alter the flexibility of the Notch extracellular domain.