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. 2007 Mar 1;26(6):1702–1712. doi: 10.1038/sj.emboj.7601616

Figure 6.

Figure 6

Model of the γ-secretase cleavage mechanism on dimeric APP TMSs. (A) Sequential γ-secretase cleavages proceed from the C terminal end to the N terminus. The ɛ- and ζ-cleavage are suggested to occur independently of the dimeric or monomeric form of the substrate (green scissors). G29 and G33 form the cross point of two APP–TMS helices and represent a sterical hindrance for the proceeding γ-secretase such that the main final cleavages occur after residue 42/40 and produce mainly Aβ42 and Aβ40 (orange scissors). Thus, the following cleavages only generate Aβ38 and Aβ37 if not inhibited by the helix–helix interactions of the dimer (red scissors). (B) Perturbed dimers (indicated by G29/G33 to alanine substitutions) resolve the sterical hindrance and allow the γ-secretase to proceed to further N-terminal sites, yielding Aβ38 and Aβ37, and Aβ34 and Aβ35 (green scissors). Thus, the site of the final cleavage is determined by the strength of interaction of the two helices of two APP molecules mediated by the TMS residues G29 and G33.