Evidence for dimeric BACE-mediated APP processing

β-Secretase (BACE) is an aspartyl protease, which proteolytically processes amyloid precursor protein, making BACE an interesting pharmacological target in Alzheimer’s disease. To study the enzymatic function of BACE, we mutated either of the two aspartic acid residues in the active site of BACE. Th...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2010-02, Vol.393 (1), p.21-27
Main Authors: Jin, Shaobo, Agerman, Karin, Kolmodin, Karin, Gustafsson, Elin, Dahlqvist, Camilla, Jureus, Anders, Liu, Gang, Fälting, Johanna, Berg, Stefan, Lundkvist, Johan, Lendahl, Urban
Format: Article
Language:English
Subjects:
Alzheimer Disease - enzymology
Alzheimer’s disease
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - genetics
Amyloid Precursor Protein Secretases - metabolism
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - metabolism
Aspartyl protease
Catalytic Domain - genetics
Endosome
Hydrophobic and Hydrophilic Interactions
Medicin och hälsovetenskap
Mice
Mice, Knockout
Mutation
Protein Multimerization
β-Secretase
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Summary:β-Secretase (BACE) is an aspartyl protease, which proteolytically processes amyloid precursor protein, making BACE an interesting pharmacological target in Alzheimer’s disease. To study the enzymatic function of BACE, we mutated either of the two aspartic acid residues in the active site of BACE. This rendered BACE functionally inactive without affecting the degree of glycosylation or endosomal localization. In contrast, substituting both active site aspartic acid residues produced a functionally inactive, endoplasmic reticulum-retained and partially glycosylated BACE. Interestingly, co-expression of the two single active site mutants partially restored β-site cleavage of amyloid precursor protein, and the restored activity was inhibited with similar dose-dependency and potency as wildtype BACE by a small molecule inhibitor raised against BACE. In sum, our data suggest that two different active site mutants can complement each other in a partially functional BACE dimer and mediate APP processing.
ISSN:0006-291X
1090-2104
1090-2104
DOI:10.1016/j.bbrc.2010.01.064