Editing Notch signaling pathway (section)

=== Ligand interactions ===
[[File:N1 dll4 cells.png|thumb|455x455px|Crystal structure of the Notch1-DLL4 complex depicted as the interaction is predicted to occur between two cells (PDB ID: 4XLW)]]
Notch signaling is initiated when Notch receptors on the cell surface engage ligands presented ''in trans'' on opposing cells''.'' Despite the expansive size of the Notch extracellular domain, it has been demonstrated that EGF domains 11 and 12 are the critical determinants for interactions with Delta.<ref>{{cite journal | vauthors = Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S | title = Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor | journal = Cell | volume = 67 | issue = 4 | pages = 687–699 | date = November 1991 | pmid = 1657403 | doi = 10.1016/0092-8674(91)90064-6 | s2cid = 12643727 }}</ref> Additional studies have implicated regions outside of Notch EGF11-12 in ligand binding. For example, Notch EGF domain 8 plays a role in selective recognition of Serrate/Jagged<ref>{{cite journal | vauthors = Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S | title = Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor | journal = Cell | volume = 67 | issue = 4 | pages = 687–699 | date = November 1991 | pmid = 1657403 | doi = 10.1016/0092-8674(91)90064-6 | s2cid = 12643727 | bibcode = 2012Sci...338.1229Y }}</ref> and EGF domains 6-15 are required for maximal signaling upon ligand stimulation.<ref>{{Cite journal|date=2013|title=Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1|journal=Journal of Biological Chemistry}}</ref> A crystal structure of the interacting regions of Notch1 and Delta-like 4 (Dll4) provided a molecular-level visualization of Notch-ligand interactions, and revealed that the N-terminal MNNL (or C2) and DSL domains of ligands bind to Notch EGF domains 12 and 11, respectively.<ref name="Luca_2015">{{cite journal | vauthors = Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC | title = Structural biology. Structural basis for Notch1 engagement of Delta-like 4 | journal = Science | volume = 347 | issue = 6224 | pages = 847–853 | date = February 2015 | pmid = 25700513 | pmc = 4445638 | doi = 10.1126/science.1261093 | bibcode = 2015Sci...347..847L }}</ref> The Notch1-Dll4 structure also illuminated a direct role for Notch O-linked fucose and glucose moieties in ligand recognition, and rationalized a structural mechanism for the glycan-mediated tuning of Notch signaling.<ref name="Luca_2015" />