Processing of beta-secretase by furin and other members of the proprotein convertase family.
The amyloid peptide is the main constituent of the amyloid plaques in brain of Alzheimer's disease patients. This peptide is generated from the amyloid precursor protein by two consecutive cleavages. Cleavage at the N terminus is performed by the recently discovered beta-secretase (Bace). This aspartyl protease contains a propeptide that has to be removed to obtain mature Bace. Furin and other members of the furin family of prohormone convertases are involved in this process. Surprisingly, beta-secretase activity, neither at the classical Asp(1) position nor at the Glu(11) position of amyloid precursor protein, seems to be controlled by this maturation step. Furthermore, we show that Glu(11) cleavage is a function of the expression level of Bace, that it depends on the membrane anchorage of Bace, and that Asp(1) cleavage can be followed by Glu(11) cleavage. Our data suggest that pro-Bace could be active as a beta-secretase in the early biosynthetic compartments of the cell and could be involved in the generation of the intracellular pool of the amyloid peptide. We conclude that modulation of the conversion of pro-Bace to mature Bace is not a relevant drug target to treat Alzheimer's disease.
Creemers
J W
JW
Center for Human Genetics, Molecular Oncology and Neuronal Cell Biology Laboratories, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Ines Dominguez
D
D
Plets
E
E
Serneels
L
L
Taylor
N A
NA
Multhaup
G
G
Craessaerts
K
K
Annaert
W
W
De Strooper
B
B
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D045683:Furin; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D011499:Protein Processing, Post-Translational; D013381:Subtilisins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D013381:Subtilisins; D045683:Furin; D016282:Aspartic Acid Endopeptidases