FIGURE 4: Stepwise cleavage model of APP. (A) The two product lines leading to the generation of Aβ40 and Aβ42 are depicted. In the major product line Aβ40 is generated by consecutive tripeptide-releasing cleavages (green) at the ε-49, ζ-46 and γ-43 sites. In a minor product line, Aβ42 is generated in a similar manner by consecutive cleavages (red) at the ε-48 and ζ-45 sites. (B) Besides γ-byproducts from the two main product lines (green and red) including a hexapeptide resulting from direct cleavage of Aβ49 to Aβ43, multiple additional minor peptides have been identified suggesting multiple product line crossings. The pentapeptide resulting from cleavage of Aβ43 to Aβ38 is indicated in purple. (C) Sequential cleavage continuously requires sterically compatible interactions of P2´ residues with the S2´ enzyme subsite of γ-secretase; major product line shown. The adjacent P4´ residue K53 is additionally presented for the comparison of side chain proportions.