Figure 1.

Schematic diagrams of the β-amyloid precursor protein (APP) and its principal metabolic derivatives. The upper diagram depicts the largest of the known APP alternate splice forms, comprising 770 amino acids. Regions of interest are indicated at their correct relative positions. A 17-residue signal peptide occurs at the amino terminus (box with vertical lines). Two alternatively spliced exons of 56 and 19 amino acids are inserted at residue 289; the first contains a serine protease inhibitor domain of the Kunitz type (KPI). A single membrane-spanning domain (TM) at amino acids 700–723 is indicated by the vertical dotted lines. The amyloid β-protein (Aβ) fragment includes 28 residues just outside the membrane plus the first 12–14 residues of the transmembrane domain. In the middle diagram, the arrow indicates the site (after residue 687; same site as the white dot in the Aβ region of APP in the upper diagram) of a constitutive proteolytic cleavage made by protease(s) designated α-secretase that enables secretion of the large, soluble ectodomain of APP (APP_s- α) into the medium and retention of the 83 residue carboxy-terminal fragment in the membrane. The C83 fragment can undergo cleavage by protease called γ-secretase at residue 711 or residue 713 to release the p3 peptides. The lower diagram depicts the alternative proteolytic cleavage after residue 671 by enzyme called β-secretase that results in the secretion of the slightly truncated APP_s- β molecule and the retention of a 99-residue carboxy-terminal fragment. The C99 fragment can also undergo heterogenous cleavages by γ-secretase to release the Aβ peptides.