University of Tasmania
Browse
Small_Neurodegener_Dis.pdf (1.36 MB)

Regulation of proBACE1 by glycosaminoglycans

Download (1.36 MB)
Version 2 2023-06-23, 11:07
Version 1 2023-05-26, 16:14
journal contribution
posted on 2023-06-23, 11:07 authored by David SmallDavid Small, DW Klaver, M Beckman
The β-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. Copyright © 2008 S. Karger AG.

History

Publication title

Neurodegenerative Diseases

Volume

5

Issue

3-4

Article number

3-4'

Number

3-4'

Pagination

206-208

ISSN

1660-2854

Department/School

Menzies Institute for Medical Research

Publisher

Karger Publishers

Publication status

  • Published

Repository Status

  • Open

Socio-economic Objectives

200502 Health related to ageing

Usage metrics

    University Of Tasmania

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC