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- Title
Cleavage of Amyloid-β Precursor Protein (APP) by Membrane-Type Matrix Metalloproteinases.
- Authors
Ahmad, Munirah; Takino, Takahisa; Miyamori, Hisashi; Yoshizaki, Tomokazu; Furukawa, Mitsuru; Sato, Hiroshi
- Abstract
Amyloid-β precursor protein (APP) was identified on expression cloning from a human placenta cDNA library as a gene product that modulates the activity of membrane-type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with APP in HEK293T cells induced cleavage and shedding of the APP ectodomain when co-expressed with APP adaptor protein Fe65. Among the MT-MMPs tested, MT3-MMP and MT5-MMP also caused efficient APP shedding. The recombinant APP protein was cleaved by MT3-MMP in vitro at the A463-M464, N579-M580, H622-S623, and H685-Q686 peptide bonds, which included a cleavage site within the amyloid β peptide region known to produce a C-terminal fragment. The Swedish-type mutant of APP, which produces a high level of amyloid β peptide, was more effectively cleaved by MT3-MMP than wild-type APP in both the presence and absence of Fe65; however, amyloid β peptide production was not affected by MT3-MMP expression. Expression of MT3-MMP enhanced Fe65-dependent transactivation by APP fused to the Gal4 DNA–binding and transactivation domains. These results suggest that MT1-MMP, MT3-MMP and MT5-MMP should play an important role in the regulation of APP functions in tissues including the central nervous system.
- Subjects
AMYLOID; DNA; METALLOPROTEINASES; PEPTIDES; CENTRAL nervous system
- Publication
Journal of Biochemistry, 2006, Vol 139, Issue 3, p517
- ISSN
0021-924X
- Publication type
Article
- DOI
10.1093/jb/mvj054