title: Evidence for dimeric BACE-mediated APP processing.
abstract: beta-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 beta-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.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Jin
authors.forename: Karin
authors.initials: K
authors.lastname: Agerman
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Elin
authors.initials: E
authors.lastname: Gustafsson
authors.forename: Camilla
authors.initials: C
authors.lastname: Dahlqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Jureus
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Johanna
authors.initials: J
authors.lastname: Fälting
authors.forename: Stefan
authors.initials: S
authors.lastname: Berg
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain / Q000235:genetics; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D055503:Protein Multimerization
chemical_list: D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse