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The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with pre-fibrillar structures

Journal Article


Abstract


  • Clusterin is an extracellular chaperone present in all disease-associated extracellular amyloid deposits, however, its roles in amyloid formation and protein deposition in vivo are poorly understood. The current study initially aimed to characterise the effects of clusterin on amyloid formation in vitro by a panel of eight protein substrates. Two of the substrates (Alzheimer's beta peptide and a PI3-SH3 domain) were then used in further experiments to examine the effects of clusterin on amyloid cytotoxicity and to probe the mechanism of clusterin action. We show that clusterin exerts potent effects on amyloid formation, the nature and extent of which vary greatly with the clusterin:substrate ratio, and provide evidenc that these effects are exerted via interactions with pre-fibrillar species that share common structural features. Pro-amyloidogenic effects of clusterin appear to be restricted to conditions in which the substrate protein is present at a very large molar excess; under these same conditions clusterin co-incorporates with substrate protein into insoluble aggregates. However, when clusterin is present at much higher but still sub-stoichiometric levels (e.g. a molar ratio of clusterin:substrate = 1:10), it potently inhibits amyloid formation and provides substantial cytoprotection. These findings suggest that clusterin is an important element in the control of extracellular protein misfolding.

Publication Date


  • 2007

Citation


  • Yerbury, J., Poon, S., Meehan, S., Thompson, B. C., Kumita, J. R., Dobson, C. M. & Wilson, M. R. (2007). The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with pre-fibrillar structures. The FASEB Journal, 21 (10), 2312-2322.

Scopus Eid


  • 2-s2.0-34547823043

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4021

Has Global Citation Frequency


Number Of Pages


  • 10

Start Page


  • 2312

End Page


  • 2322

Volume


  • 21

Issue


  • 10

Abstract


  • Clusterin is an extracellular chaperone present in all disease-associated extracellular amyloid deposits, however, its roles in amyloid formation and protein deposition in vivo are poorly understood. The current study initially aimed to characterise the effects of clusterin on amyloid formation in vitro by a panel of eight protein substrates. Two of the substrates (Alzheimer's beta peptide and a PI3-SH3 domain) were then used in further experiments to examine the effects of clusterin on amyloid cytotoxicity and to probe the mechanism of clusterin action. We show that clusterin exerts potent effects on amyloid formation, the nature and extent of which vary greatly with the clusterin:substrate ratio, and provide evidenc that these effects are exerted via interactions with pre-fibrillar species that share common structural features. Pro-amyloidogenic effects of clusterin appear to be restricted to conditions in which the substrate protein is present at a very large molar excess; under these same conditions clusterin co-incorporates with substrate protein into insoluble aggregates. However, when clusterin is present at much higher but still sub-stoichiometric levels (e.g. a molar ratio of clusterin:substrate = 1:10), it potently inhibits amyloid formation and provides substantial cytoprotection. These findings suggest that clusterin is an important element in the control of extracellular protein misfolding.

Publication Date


  • 2007

Citation


  • Yerbury, J., Poon, S., Meehan, S., Thompson, B. C., Kumita, J. R., Dobson, C. M. & Wilson, M. R. (2007). The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with pre-fibrillar structures. The FASEB Journal, 21 (10), 2312-2322.

Scopus Eid


  • 2-s2.0-34547823043

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4021

Has Global Citation Frequency


Number Of Pages


  • 10

Start Page


  • 2312

End Page


  • 2322

Volume


  • 21

Issue


  • 10