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Pro-domain removal in ASP-2 and the cleavage of the amyloid precursor are influenced by pH.

Sidera, C; Liu, C; Austen, B (2002) Pro-domain removal in ASP-2 and the cleavage of the amyloid precursor are influenced by pH. BMC Biochemistry, 3 (25). ISSN 1471-2091 https://doi.org/10.1186/1471-2091-3-25
SGUL Authors: Austen, Brian Maxwell

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Abstract

BACKGROUND: One of the signatures of Alzheimer's disease is the accumulation of aggregated amyloid protein, Abeta, in the brain. Abeta arises from cleavage of the Amyloid Precursor protein by beta and gamma secretases, which present attractive candidates for therapeutic targeting. Two beta-secretase candidates, ASP-1 and ASP-2, were identified as aspartic proteases, both of which cleave the amyloid precursor at the beta-site. These are produced as immature transmembrane proteins containing a pro-segment. RESULTS: ASP-2 expressed in HEK293-cells cleaved the Swedish mutant amyloid precursor at different beta-sites at different pHs in vitro. Recent reports show that furin cleaves the pro-peptide of ASP-2, whereas ASP-1 undergoes auto-catalysis. We show that purified recombinant ASP-2 cleaves its own pro-peptide at ph 5 but not pH 8.5 as seen by mass spectrometry, electrophoresis and N-terminal sequencing. CONCLUSION: We suggest that ASP-2 processing as well as activity are influenced by pH, and hence the cellular localisation of the protein may have profound effects on the production of Abeta. These factors should be taken into consideration in the design of potential inhibitors for these enzymes.

Item Type: Article
Additional Information: PMCID: PMC126479 © 2002 Sidera et al; licensee BioMed Central Ltd. This article is published in Open Access: verbatim copying and redistribution of this article are permitted in all media for any non-commercial purpose, provided this notice is preserved along with the article's original URL.
Keywords: Amino Acid Sequence, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Aspartic Acid Endopeptidases, Cell Line, Humans, Hydrogen-Ion Concentration, Hydrolysis, Molecular Sequence Data, Protein Structure, Tertiary
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: BMC Biochemistry
ISSN: 1471-2091
Dates:
DateEvent
31 August 2002Published
PubMed ID: 12204094
Web of Science ID: 12204094
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URI: http://openaccess.sgul.ac.uk/id/eprint/1767
Publisher's version: https://doi.org/10.1186/1471-2091-3-25

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