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Development and characterization of a novel membrane assay for full-length BACE-1 at pH 6.0.
Abstract
β-Site amyloid precursor protein cleaving enzyme-1 (BACE-1) is a transmembrane aspartic protease that mediates the initial cleavage of the amyloid precursor protein (APP), leading to the generation of amyloid-β (Aβ) peptides that are thought to be causative of Alzheimer's disease (AD). Consequently, inhibition of BACE-1 is an attractive therapeutic approach for the treatment of AD. In general, in vitro biochemical assays to monitor BACE-1 activity have used the extracellular domain of the protein that contains the catalytic active site. This form of BACE-1 is catalytically active at acidic pH and cleaves APP-based peptide substrates at the β-site. However, this form of BACE-1 does not mimic the natural physiology of BACE-1 and shows minimal activity at pH 6.0, which is more representative of the pH within the intracellular compartments where BACE-1 resides. Moreover, high-throughput screens with recombinant BACE-1 at pH 4.5 have failed to identify tractable leads for drug discovery, and hence, BACE-1 inhibitor development has adopted a rational drug design approach. Here we describe the development and validation of a novel membrane assay comprising full-length BACE-1 with measurable activity at pH 6.0, which could be used for the identification of novel inhibitors of BACE-1.
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BACE-1 requires an acidic environment (optimum pH 4.5) to be enzymatically active.
“This type I transmembrane protein of the aspartyl proteinase family needs an acidic environment (optimum pH 4.5) to be enzymatically active (Saric et al., 2013).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Saric et al., 2013
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Cited by
Sorted by citations
García-González, L., Pilat, D., Baranger, K., & Rivera, S. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00244 · Cited by 88
Metadata
- Authors
- Saric, A., Brügge, L. Z., Müller-Pompalla, D., Rysiok, T., Ousson, S., Permanne, B., Quattropani, A., Busch, M., Beher, D., & Hussain, I.
- Venue
- SLAS Discovery
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 18
- Issue
- 3
- Pages
- 277-285
- ISSN
- 2472-5552
- Cited by
- 4
- References
- 0
- Language
- en
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