Fig. 1.

APP processing, FAD mutations, and β-site APP cleaving enzyme (BACE)1. (a) APP is a type-I membrane protein that is sequentially cleaved by two aspartic proteases to generate Aβ. First, the β-secretase enzyme (β) cuts APP (1) to create the N-terminus of Aβ. Two APP fragments are produced: membrane-bound C99 and secreted sAPPβ ectodomain (yellow). Second, C99 is cleaved by the γ-secretase enzyme (γ) to generate the C-terminus of Aβ. Aβ (orange) is then released into the lumen of the endosome and secreted into the extracellular medium. An intracellular domain, C59 (green), is also produced. (b) The membrane-bound APP polypeptide is represented by the gray string. APP residues that affect β-secretase processing of APP in humans are represented by gray circles, within which the wild-type residue is identified by the single-letter amino acid code. The K670N/M671L (Swedish) and A673V mutations cause FAD by increasing the rate of β-secretase cleavage and Aβ production, whereas the A673T mutation protects against Alzheimer’s disease (AD) by doing the opposite. All three mutations occur at or within one amino acid of the β-secretase cleavage site. Red, blue, and lavender notched ellipses represent α, β, and γ-secretases, respectively, cutting at their respective cleavage sites in APP. (c) BACE1 is a 501 amino acid type-I transmembrane aspartic protease. The various subdomains of BACE1 are indicated to the right of the structure. Numbers and letters refer to amino acid positions and single-letter code, respectively. The two signature aspartic protease active site motifs at positions 93 and 289 are shaded black. S–S denote positions of disulfide bridges within the catalytic domain; N represents positions of N-linked glycosylation sites; R indicates positions of acetylated arginine residues; C marks positions of S-palmitoylated cysteine residues; P indicates phosphorylation of serine 498; Ub denotes ubiquitination of lysine 501.