Suppression of apolipoprotein C-II amyloid formation by the extracellular chaperone, clusterin.
The effect of the extracellular chaperone, clusterin, on amyloid fibril formation by lipid-free human apolipoprotein C-II (apoC-II) was investigated. Sub-stoichiometric levels of clusterin, derived from either plasma or semen, potently inhibit amyloid formation by apoC-II. Inhibition is dependent on apoC-II concentration, with more effective inhibition by clusterin observed at lower concentrations of apoC-II. The average sedimentation coefficient of apoC-II fibrils formed from apoC-II (0.3 mg.mL-1) is reduced by coincubation with clusterin (10 microg x mL(-1)). In contrast, addition of clusterin (0.1 mg x mL(-1)) to preformed apoC-II amyloid fibrils (0.3 mg x mL(-1)) does not affect the size distribution after 2 days. This sedimentation velocity data suggests that clusterin inhibits fibril growth but does not promote fibril dissociation. Electron micrographs indicate similar morphologies for amyloid fibrils formed in the presence or absence of clusterin. The substoichiometric nature of the inhibition suggests that clusterin interacts with transient amyloid nuclei leading to dissociation of the monomeric subunits. We propose a general role for clusterin in suppressing the growth of extracellular amyloid.
Hatters
Danny M
DM
Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria, Australia.
Wilson
Mark R
MR
Easterbrook-Smith
Simon B
SB
Howlett
Geoffrey J
GJ
D000682:Amyloid / Q000378:metabolism*; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000378:metabolism* / Q000648:ultrastructure; D052160:Benzothiazoles; D051152:Clusterin; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism
D000682:Amyloid; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D052160:Benzothiazoles; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D013844:Thiazoles; C009462:thioflavin T