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BACE2, a β -Secretase Homolog, Cleaves at the β Site and within the amyloid-β Region of the amyloid-β Precursor Protein
Michael Farzan, Christine E. Schnitzler, Natalya Vasilieva, Doris Leung and Hyeryun Choe
Proceedings of the National Academy of Sciences of the United States of America
Vol. 97, No. 17 (Aug. 15, 2000), pp. 9712-9717
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/123529
Page Count: 6
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Production of amyloid-β protein (Aβ ) is initiated by a β -secretase that cleaves the Aβ precursor protein (APP) at the N terminus of Aβ (the β site). A recently identified aspartyl protease, BACE, cleaves the β site and at residue 11 within the Aβ region of APP. Here we show that BACE2, a BACE homolog, cleaves at the β site and more efficiently at a different site within Aβ . The Flemish missense mutation of APP, implicated in a form of familial Alzheimer's disease, is adjacent to this latter site and markedly increases Aβ production by BACE2 but not by BACE. BACE and BACE2 respond identically to conservative β -site mutations, and alteration of a common active site Arg inhibits β -site cleavage but not cleavage within Aβ by both enzymes. These data suggest that BACE2 contributes to Aβ production in individuals bearing the Flemish mutation, and that selective inhibition of these highly similar proteases may be feasible and therapeutically advantageous.
Proceedings of the National Academy of Sciences of the United States of America © 2000 National Academy of Sciences