Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase

The enzyme BACE (beta-site APP-cleaving enzyme) has recently been identifie d as the beta-secretase that cleaves the amyloid precursor protein (APP) to produce the N terminus of the A beta peptide found in plaques in the brain s of Alzheimer's disease patients. BACE is an aspartic protease similar to pepsin and renin. Comparative modeling of the three-dimensional structure o f BACE in complex with its substrate shows that several residues confer spe cificity of the enzyme for APP. In particular, Arg296 forms a salt-bridge w ith the P1' Asp of the APP substrate, explaining the unusual preference of BACE among aspartic proteases for a P1' residue that is negatively charged. Several hydrophobic residues in the enzyme form a pocket for the P1 hydrop hobic residue (Met in wild-type APP and Leu in APP with the "Swedish mutati on" associated with early-onset of Alzheimer's disease). Inhibitors that ca n bind to the BACE active site may prove useful for drugs to treat and prev ent Alzheimer's disease. (C) 2000 Academic Press.