title: Identification of a novel aspartic protease (Asp 2) as beta-secretase.
abstract: The Alzheimer's disease beta-amyloid peptide (Abeta) is produced by excision from the type 1 integral membrane glycoprotein amyloid precursor protein (APP) by the sequential actions of beta- and then gamma-secretases. Here we report that Asp 2, a novel transmembrane aspartic protease, has the key activities expected of beta-secretase. Transient expression of Asp 2 in cells expressing APP causes an increase in the secretion of the N-terminal fragment of APP and an increase in the cell-associated C-terminal beta-secretase APP fragment. Mutation of either of the putative catalytic aspartyl residues in Asp 2 abrogates the production of the fragments characteristic of cleavage at the beta-secretase site. The enzyme is present in normal and Alzheimer's disease (AD) brain and is also found in cell lines known to produce Abeta. Asp 2 localizes to the Golgi/endoplasmic reticulum in transfected cells and shows clear colocalization with APP in cells stably expressing the 751-amino-acid isoform of APP.
authors.affiliation: Department of Neurosciences, SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Hussain
authors.forename: D
authors.initials: D
authors.lastname: Powell
authors.forename: D R
authors.initials: DR
authors.lastname: Howlett
authors.forename: D G
authors.initials: DG
authors.lastname: Tew
authors.forename: T D
authors.initials: TD
authors.lastname: Meek
authors.forename: C
authors.initials: C
authors.lastname: Chapman
authors.forename: I S
authors.initials: IS
authors.lastname: Gloger
authors.forename: K E
authors.initials: KE
authors.lastname: Murphy
authors.forename: C D
authors.initials: CD
authors.lastname: Southan
authors.forename: D M
authors.initials: DM
authors.lastname: Ryan
authors.forename: T S
authors.initials: TS
authors.lastname: Smith
authors.forename: D L
authors.initials: DL
authors.lastname: Simmons
authors.forename: F S
authors.initials: FS
authors.lastname: Walsh
authors.forename: C
authors.initials: C
authors.lastname: Dingwall
authors.forename: G
authors.initials: G
authors.lastname: Christie
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D010450:Endopeptidases; D005260:Female; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010206:Papain / Q000737:chemistry; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010206:Papain; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; D002402:Cathepsin D