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Glycosaminoglycan-induced activation of the β-secretase (BACE1) of Alzheimer's disease

Citation

Klaver, DW and Wilce, MCJ and Gasperini, R and Freeman, C and Juliano, JP and Parish, C and Foa, L and Aguilar, MI and Small, DH, Glycosaminoglycan-induced activation of the β-secretase (BACE1) of Alzheimer's disease, Journal of Neurochemistry, 112, (6) pp. 1552-1561. ISSN 0022-3042 (2010) [Refereed Article]


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The definitive published version is available online at: http://interscience.wiley.com

DOI: doi:10.1111/j.1471-4159.2010.06571.x

Abstract

The b-site APP cleaving enzyme (BACE1) is responsible for the first step in the production of the b-amyloid protein of Alzheimer’s disease. BACE1 is synthesized as a partially active zymogen (proBACE1). We previously showed that the glycosaminoglycan (GAG) heparin can increase the enzyme activity of proBACE1. In this study, the structural requirements and the mechanism for the GAG-induced activation were examined. The effect of heparin on proBACE1 was influenced by the degree of sulfation and carboxylation of the GAG, as well as by the length of the sugar. Although low molecular weight heparin fragments did not strongly stimulate proBACE1, they inhibited heparin-induced activation of the enzyme. The structure of the zymogen was modeled using the known X-ray structures of the BACE1 catalytic domain and the homologous prodomain of porcine pepsinogen. The modeled structure suggested that a heparin-binding domain may reside close to the prodomain, and that movement of a loop region between residues 46–65, lying adjacent to the prodomain, may be needed to accommodate heparin binding. The presence of the loop domain adjacent to the active site may account for the lower activity of the zymogen relative to the mature enzyme. Movement of the loop region upon heparin binding could expose the active site region to allow for increased substrate binding. The results suggest a model in which conformational changes close to the prodomain may be involved in the mechanism of heparin-induced activation of proBACE1.

Item Details

Item Type:Refereed Article
Keywords:b-secretase, Alzheimer’s disease, amyloid, glycosaminoglycan, heparin, protease
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Neurosciences not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Neurodegenerative Disorders Related to Ageing
Author:Klaver, DW (Mr David Klaver)
Author:Gasperini, R (Dr Rob Gasperini)
Author:Foa, L (Professor Lisa Foa)
Author:Small, DH (Professor David Small)
ID Code:64812
Year Published:2010
Web of Science® Times Cited:15
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-09-02
Last Modified:2012-03-01
Downloads:0

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