Format

Send to:

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9712-7.

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

Author information

  • 1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. farzan@mbcrr.harvard.edu

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.

PMID:
10931940
[PubMed - indexed for MEDLINE]
PMCID:
PMC16930
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk