1. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.
- Author
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Farzan M, Schnitzler CE, Vasilieva N, Leung D, and Choe H
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Amino Acid Sequence, Amino Acid Substitution genetics, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor chemistry, Amyloid beta-Protein Precursor genetics, Arginine genetics, Arginine metabolism, Aspartic Acid Endopeptidases chemistry, Aspartic Acid Endopeptidases genetics, Binding Sites, Cell Line, Cloning, Molecular, Endopeptidases, Gene Expression Profiling, Humans, Hydrogen-Ion Concentration, Molecular Sequence Data, Mutation, Missense genetics, Nervous System enzymology, Netherlands, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Phenylalanine metabolism, RNA, Messenger analysis, RNA, Messenger genetics, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Homology, Amino Acid, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Substrate Specificity, Sweden, Amyloid beta-Protein Precursor metabolism, Aspartic Acid Endopeptidases metabolism, Protein Processing, Post-Translational
- Abstract
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.
- Published
- 2000
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