Figure 7.

Cartoon Representation of Possible Notch/Ligand Interactions and the Effect of Addition of EGF10 on the Interaction of EGF11-13 with Ligand

(A) Notch EGF11/EGF12 and Dll-4 DSL/C2 domains have been shown to interact at two sites (Luca et al., 2015). Our near-linear orientation for hN1 EGF6-9, upstream of the flexible linkage at EGF9-10 (indicated by the blue arrow above the linker), suggests that Notch may align with ligand along its longitudinal axis. The Ca²⁺-binding EGF domains are shown in green, other EGF domains in wheat, the DSL domain in yellow, and the C2 domain in blue. The Dll-1, Dll-4, J1, and J2 ligands all share the C2-DSL-EGF1-3 architecture. Dll-1 and Dll-4 have a further five EGFs while J1 and J2 have a further 13 EGFs.

(B) In the X-ray structure of the Notch/Dll-4 complex, where EGF11 is in a non-native context (not bound to EGF10), EGF11 makes many more stabilizing contacts with DSL than EGF12 does with the C2 domain. The vertical lines in gray indicate stabilizing interactions between pairs of domains.

(C) It is plausible that covalent linkage of EGF10 to EGF11-13 results in a steric clash between EGF10 and EGF1, and that small rearrangements that occur upon interaction with Dll-4 could disrupt some EGF11-mediated contacts within the N-terminal region of this domain. New contacts made between EGF10 and EGF1 are not sufficient to overcome the loss of EGF11-mediated contacts, since Notch EGF10-13 binds less well to Dll-4 than EGF11-13. The dashed gray line and the ? are used to indicate a possible interaction.