APP processing pathway and and domain organization of β-secretase. (a) A schematic representation of the sequential cleavages of APP at the β- and γ- sites to generate β-amyloid. APP and β-secretase are both integral membrane proteins with type 1 orientation, γ-secretase is probably PS 1, a protein with eight TM domains (not shown). Recent data indicates that these three proteins assemble in conjunction with Nicastrin, a protein which interacts with PS1, in cholesterol rich microdomains in cellular membranes. (b) The amyloid domain of APP showing the mutations which are associated with early onset familial forms of AD, highlighting those which occur at the secretase cleavage sites. The beginning of the TM domain is shown. (c) Domain organization of β-secretase. The protein has a cleaved signal peptide, a prodomain and a catalytic domain in which the catalytic aspartic residues are located. The catalytic domain shows the 3 di-sulfide bridges characteristic of the pepsin family of aspartic proteinases and is glycosylated at 4 sites. The cytoplasmic tail contains a di-leucine endosomal retreival signal, cysteine residues which are palmitoylated and phosphorylation sites. The homolog, Asp1 (DRAP, BACE2) shows the same overall structural organization.