Regulation of proBACE1 by glycosaminoglycans.
The beta-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 microg/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.
Small
David H
DH
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia. d.h.small@menzies.utas.edu.au
Klaver
David W
DW
Beckman
Marie
M
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans
D004792:Enzyme Precursors; D019812:Heparan Sulfate Proteoglycans; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human