Identification of a novel aspartic protease (Asp 2) as beta-secretase.
Hussain I,
Powell D,
Howlett DR,
Tew DG,
Meek TD,
Chapman C,
Gloger IS,
Murphy KE,
Southan CD,
Ryan DM,
Smith TS,
Simmons DL,
Walsh FS,
Dingwall C,
Christie G.
Department of Neurosciences, SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom.
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.
PMID: 10656250 [PubMed - indexed for MEDLINE]