Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch

The intramembrane cleavage of beta -amyloid precursor protein by gamma -secretase is the final step in the generation of amyloid beta -protein. A 59- or 57-residue C-terminal fragment called CTF gamma is produced concomitantly. Putative CTF gamma generated in rat brain membrane preparations was purified and sequenced. Instead of CTF gamma, shorter 50- and 49-residue fragments were identified. In addition, we found similar C-terminal fragments of beta -amyloid precursor-like proteins 1 and 2; these were also cleaved at corresponding sites. This newly identified cleavage occurs at a site two to five residues inside the cytoplasmic membrane boundary, which is very similar to gamma -secretase-like cleavage of Notch 1.