Basic Science and Pathogenesis.

Background: Successive cleavages of amyloid precursor protein C-terminal 99 residues (APP-C99) by human γ-secretase result in amyloid-β peptides (Aβs) of varying lengths, the main constituents of amyloid plaques in Alzheimer's disease patients. Most cleavages have a step size of three residues, as exemplified by sequential generation of Aβ49, Aβ46, Aβ43, and Aβ40.

Method: To elucidate the mechanism of substrate cleavage, we determined atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43.

Result: Remarkably, in all cases, the substrate has the same structural features: a transmembrane α-helix that binds PS1, a three-residue linker, and a β-strand that forms a hybrid β-sheet with two β-strands of PS1. Proteolytic cleavage occurs at the peptide bond just preceding the substrate β-strand.

Conclusion: Therefore, each cleavage is followed by unwinding of the substrate α-helix by one turn, translocation of the α-helix towards the C-terminus, and formation of a new β-strand. This mechanism is consistent with existing biochemical data and may also explain the cleavages of other substrates by human γ-secretase.