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Regulation of proBACE1 by glycosaminoglycans

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Small, DH and Klaver, DW and Beckman, M (2008) Regulation of proBACE1 by glycosaminoglycans. Neurodegenerative Diseases, 5 (3-4). pp. 206-208. ISSN 1660-2854

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Abstract

The -secretase (BACE1) is initially synthesized as a partially active zymogen containing a prodomain which can be further activated through proteolytic cleavage of the prodomain by a furin-like protease. The active site of BACE1 is large and although a number of high-affinity active-site inhibitors of BACE1 have been described, most of these compounds are large, polar and do not cross the blood-brain barrier. However, it may be possible to target other regions of the protein which regulate BACE1 allosterically. We have found that proBACE1 can be stimulated by relatively low concentrations (e.g. 1 µg/ml) of heparin. Heparin initially increases proBACE1 activity, probably by binding to the prodomain, which decreases steric inhibition at the active site. However, the heparin-activated zymogen also undergoes autocatalysis, which ultimately leads to a loss of enzyme activity. We speculate that proBACE1 can be regulated by endogenous heparan sulfate proteoglycans and that drugs which target this interaction may have value in the treatment of Alzheimer's disease.

Item Type: Article
Keywords: Secretase,Glycosaminoglycan,Heparin,Proteolysis,Amyloid processing,Amyloid
Journal or Publication Title: Neurodegenerative Diseases
Page Range: pp. 206-208
ISSN: 1660-2854
Identification Number - DOI: 10.1159/000113703
Date Deposited: 20 Nov 2008 04:11
Last Modified: 18 Nov 2014 03:53
URI: http://eprints.utas.edu.au/id/eprint/7961
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