Figure 2. Composition of the active γ-secretase complex and sites of γ-secretase cleavage in APP.

The active γ-secretase complex (left) is composed of four components: presenilin (PS, green), nicastrin (Nct, light blue), Aph-1 (dark blue), and Pen-2 (pink). PS is cleaved in the hydrophobic region (Φ) to yield the PS N- and C-terminal fragments (PS-NTF and -CTF, respectively). The catalytic aspartic acid residues, Asp257 and Asp385, are found on TMDs 6 (VI) and 7 (VII), respectively. Glu333 of the DAP domain of Nct binds the N-terminal amine of substrates for positioning in the γ-secretase active site. Endogenous Nct is heavily glycosylated (orange) in active γ-secretase complexes. The Nct·Aph-1 heterodimer binds to PS-CTF through TMD4 (iv) of Aph-1 and both the TMD and extracellular domain of Nct. Pen-2 is buried in interactions with PS-NTF, and both Pen-2 and the first TMD of PS appear to modulate the active site. A “docking site” for substrates may also exist near the active site. Inset, γ-secretase cleaves APP (yellow) at multiple sites within its transmembrane domain. The resulting Aβ peptides are named according to their length from the N-terminus. Aβ40 and Aβ42 (large, bold) represent the majority of the Aβ species produced.