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Fig. 3. X-ray structure of the human NOTCH2 NRR in the autoinhibited conformation and models for signal activation. (A) Ribbon representation of the NOTCH2 NRR. The LNR modules are colored different shades of pink and purple, and the HD domain is colored in white and turquoise; the white and turquoise represent residues that are N- and C-terminal, respectively, to the furin-cleavage loop (S1). The three bound Ca2+ ions are green, the bound Zn2+ ion is purple and the ten disulfide bonds are red. The positions of S1 and S2 cleavage are indicated with red arrows. (B) The LNR-AB linker sterically blocks access to the metalloprotease-cleavage site. The hydrophobic pocket in the HD domain that houses the S2 site is rendered in a surface representation, and residues from the LNR-AB linker are in ball-and-stick representation. (C) Model for activation by mechanical force. Endocytosis of bound ligand generates a mechanical force that tugs on the LNR domain (pink structure; 1), disengaging the hydrophobic plug from the hydrophobic pocket containing the S2 site (2) and peeling the LNR repeats away from the HD domain (white structure; 3). Partial or complete relaxation of the HD domain then allows access of the metalloprotease to the S2 site and cleavage of the scissile bond to trigger Notch activation (4). (D) Peeling of the LNR repeats (pink) away from the HD domain (white) might not confer sufficient exposure of the S2 site to allow cleavage by metalloprotease. The left panel depicts a hypothetical model for the negative regulatory region upon peeling of the first two LNR repeats away from the HD domain; the right panel shows the structure of the catalytic domain of the metalloprotease TACE (PDB ID code 1BKC). The deep active-site cleft is indicated. A and B are adapted from Gordon et al. (Gordon et al., 2007) and are reproduced with permission.
