title: ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site.
abstract: Sequential proteolytic processing of the Amyloid Precursor Protein (APP) by beta- and gamma-secretases generates the 4-kDa amyloid (A beta) peptide, a key component of the amyloid plaques seen in Alzheimer's disease (AD). We and others have recently reported the identification and characterisation of an aspartic proteinase, Asp2 (BACE), as beta-secretase. Here we describe the characterization of a second highly related aspartic proteinase, Asp1 as a second beta-secretase candidate. Asp1 is expressed in brain as detected at the mRNA level and at the protein level. Transient expression of Asp1 in APP-expressing cells results in an increase in the level of beta-secretase-derived soluble APP and the corresponding carboxy-terminal fragment. Paradoxically there is a decrease in the level of soluble A beta secreted from the cells. Asp1 colocalizes with APP in the Golgi/endoplasmic reticulum compartments of cultured cells. Asp1, when expressed as an Fc fusion protein (Asp1-Fc), has the N-terminal sequence ALEP..., indicating that it has lost the prodomain. Asp1-Fc exhibits beta-secretase activity by cleaving both wild-type and Swedish variant (KM/NL) APP peptides at the beta-secretase site.
authors.affiliation: Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow. Essex, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Hussain
authors.forename: D J
authors.initials: DJ
authors.lastname: Powell
authors.forename: D R
authors.initials: DR
authors.lastname: Howlett
authors.forename: G A
authors.initials: GA
authors.lastname: Chapman
authors.forename: L
authors.initials: L
authors.lastname: Gilmour
authors.forename: P R
authors.initials: PR
authors.lastname: Murdock
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: K
authors.initials: K
authors.lastname: Schneider
authors.forename: S J
authors.initials: SJ
authors.lastname: Ratcliffe
authors.forename: D
authors.initials: D
authors.lastname: Tattersall
authors.forename: T T
authors.initials: TT
authors.lastname: Testa
authors.forename: C
authors.initials: C
authors.lastname: Southan
authors.forename: D M
authors.initials: DM
authors.lastname: Ryan
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: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D019556:COS Cells; D003001:Cloning, Molecular; D010450:Endopeptidases; D005260:Female; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D016564:Amyloid beta-Protein Precursor; D006023:Glycoproteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human