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 identified as the beta-secretase that cleaves the amyloid precursor protein (APP) to produce the N terminus of the Abeta peptide found in plaques in the brains of Alzheimer's disease patients. BACE is an aspartic protease similar to pepsin and renin. Comparative modeling of the three-dimensional structure of BACE in complex with its substrate shows that several residues confer specificity of the enzyme for APP. In particular, Arg296 forms a salt-bridge with 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 hydrophobic residue (Met in wild-type APP and Leu in APP with the "Swedish mutation" associated with early-onset of Alzheimer's disease). Inhibitors that can bind to the BACE active site may prove useful for drugs to treat and prevent Alzheimer's disease.

Sauder JM ，Arthur JW ，Dunbrack RL Jr 《JOURNAL OF MOLECULAR BIOLOGY》

BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.

:Production of amyloid-beta protein (Abeta) is initiated by a beta-secretase that cleaves the Abeta precursor protein (APP) at the N terminus of Abeta (the beta site). A recently identified aspartyl protease, BACE, cleaves the beta site and at residue 11 within the Abeta region of APP. Here we show that BACE2, a BACE homolog, cleaves at the beta site and more efficiently at a different site within Abeta. The Flemish missense mutation of APP, implicated in a form of familial Alzheimer's disease, is adjacent to this latter site and markedly increases Abeta production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative beta-site mutations, and alteration of a common active site Arg inhibits beta-site cleavage but not cleavage within Abeta by both enzymes. These data suggest that BACE2 contributes to Abeta production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous.

Farzan M ，Schnitzler CE ，Vasilieva N ，Leung D ，Choe H ... -  《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》

Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.

Yan R ，Bienkowski MJ ，Shuck ME ，Miao H ，Tory MC ，Pauley AM ，Brashier JR ，Stratman NC ，Mathews WR ，Buhl AE ，Carter DB ，Tomasselli AG ，Parodi LA ，Heinrikson RL ，Gurney ME ... -  《NATURE》

A novel beta-site amyloid precursor protein cleaving enzyme (BACE) isoform regulated by nonsense-mediated mRNA decay and proteasome-dependent degradation.

Tanahashi H ，Tabira T 《NEUROSCIENCE LETTERS》

Prediction of the tertiary structure of the beta-secretase zymogen.

Chou KC ，Howe WJ 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》