Structural divergence between Notch1 and Notch2 NRRs. (A,B) Convergence of HD-N, HD-C, and LNR-C is mediated by a hydrogen bond in the Notch1 NRR (A) and a Zn²⁺ coordination site in the Notch2 NRR (B). (C,D) Comparison of interactions stabilizing helix 1 in the Notch1 and Notch2 NRRs. In Notch1, there is an intrahelical salt bridge and the helix is anchored to LNR-C via a single salt bridge. In Notch2, there are several electrostatic interactions between the helix and LNR-C (D). (E,F) The LNR A-B linker of the Notch1 (E) and Notch2 (F) NRRs masks the metalloprotease cleavage site. In each structure, a 3-residue sequence from the linker occludes the S2 site, even though 2 of the 3 amino acid residues comprising the protective plug are not conserved (see “Interdomain interactions” for details). Black labels identify residues participating in the interactions discussed, whereas blue labels identify residues that form analogous interactions in the other receptor.