Characterization of Alzheimer's β-secretase protein BACE: A pepsin family member with unusual properties

Mitsuru Haniu*, Paul Denis, Yunjen Young, Elizabeth A. Mendiaz, Janis Fuller, John O. Hui, Brian D. Bennett, Steven Kahn, Sandra Ross, Teresa Burgess, Viswanatham Katta, Gary Rogers, Robert Vassar, Martin Citron

*Corresponding author for this work

Research output: Contribution to journalArticle

190 Scopus citations

Abstract

The cerebral deposition of amyloid β-peptide is an early and critical feature of Alzheimer's disease. Amyloid β-peptide is released from the amyloid precursor protein by the sequential action of two proteases, β- secretase and γ-secretase, and these proteases are prime targets for therapeutic intervention. We have recently cloned a novel aspartic protease, BACE, with all the known properties of β-secretase. Here we demonstrate that BACE is an N-glycosylated integral membrane protein that undergoes constitutive N. terminal processing in the Golgi apparatus. We have used a secreted Fc fusion-form of BACE (BACE-IgG) that contains the entire ectodomain for a detailed analysis of post-translational modifications. This molecule starts at Glu46 and contains four N-glycosylation sites (Ash153, Ash172, Ash223, and Ash354). The six Cys residues in the ectodomain form three intramolecular disulfide linkages (Cys216-Cys420, Cys278-Cys443, and Cys330-Cys380). Despite the conservation of the active site residues and the 30-37% amino acid homology with known aspartic proteases, the disulfide motif is fundamentally different from that of other aspartic proteases. This difference may affect the substrate specificity of the enzyme. Taken together, both the presence of a transmembrane domain and the unusual disulfide bond structure lead us to conclude that BACE is an atypical pepsin family member.

Original languageEnglish (US)
Pages (from-to)21099-21106
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number28
DOIs
StatePublished - Jul 14 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Haniu, M., Denis, P., Young, Y., Mendiaz, E. A., Fuller, J., Hui, J. O., Bennett, B. D., Kahn, S., Ross, S., Burgess, T., Katta, V., Rogers, G., Vassar, R., & Citron, M. (2000). Characterization of Alzheimer's β-secretase protein BACE: A pepsin family member with unusual properties. Journal of Biological Chemistry, 275(28), 21099-21106. https://doi.org/10.1074/jbc.M002095200