Structure of Notch proteins and their ligands. (A) Notch receptors: Notch 1-4 are presented on the cell surface as heterodimers. (B) Notch ligands: 2 transmembrane-bound ligands for Notch have been identified in Drosophila, named Delta (Dl) and Serrate (Ser). The vertebrates possess 3 Delta homologues, called Delta-like (DLL)–1, -3 and -4, and 2 Serrate homologues, Jagged 1 (JAG1) and Jagged 2 (JAG2). Serrate, Jagged 1 and Jagged 2 harbor a cysteine-rich domain (CR) after the EGF-like repeats. Jagged 1, Jagged 2 and DLL 1 bind to all the Notch receptors; DLL 3 binds to Notch 1; DLL 4 binds to Notch 1 and Notch 4. (C) Domain structure of the heterodimer Notch receptors: the ectodomain of Notch receptors contains EGF-like repeats and a cysteine-rich Notch/Lin12 domain (LN); this is followed by a transmembrane domain, the RAM domain and 6 ankyrin repeats (ANK), 2 nuclear-localization signals (NLSs), followed by the transactivation domain (TAD) and a PEST sequence.