The type I membrane-spanning proteins Jagged (Jagged-i and -2) and Delta (Delta-l, - 3 and -4) are the human ligands of Notch receptors, which mediate key signaling events in cell differentiation and morphogenesis. The Jagged and Delta proteins are composed of a relatively large extracellular region and of a 100-150 residue, yet uncharacterized cytoplasmic tail, which has been recently found to be important in Notch bi-directional signaling. We applied bioinformatics methods to analyze the intracellular region of human Notch ligands, and to predict their structural and functional properties. We searched databases for orthologues, and found that while the intracellular region is evolutionaiy well conserved within the same ligand type, a wide variability is observed in different ligands. No significant similarity was found between the intracellular region of Jagged and Delta and proteins of known 3D structure. Globularity and disorder predictions indeed suggest that these regions are largely unstructured. However, secondary structure predictions show that these regions have some propensity to form local secondary structure elements. Functional predictions based on pattern recognition imply that the specificity in the Notch machinery response might be related to specific post-translational modifications and binding motifs in the ligand cytoplasmic tail, rather than to specific interactions between the receptors and the extracellular region of the ligands. We also speculate that, given the unusual amino acid composition, the cytoplasmic tail of Jagged and Delta might be involved in zinc binding
