pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers

Kevin W. Tipping, Theodoros K. Karamanos, Toral Jakhria, Matthew G. Iadanza, Sophia C. Goodchild, Roman Tuma, Neil A. Ranson, Eric W. Hewitt, Sheena E. Radford*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Citations (Scopus)


Amyloid disorders cause debilitating illnesses through the formation of toxic protein aggregates. The mechanisms of amyloid toxicity and the nature of species responsible for mediating cellular dysfunction remain unclear. Here, using beta(2)-microglobulin (beta(2)m) as a model system, we show that the disruption of membranes by amyloid fibrils is caused by the molecular shedding of membrane-active oligomers in a process that is dependent on pH. Using thioflavin T (ThT) fluorescence, NMR, EM and fluorescence correlation spectroscopy (FCS), we show that fibril disassembly at pH 6.4 results in the formation of nonnative spherical oligomers that disrupt synthetic membranes. By contrast, fibril dissociation at pH 7.4 results in the formation of nontoxic, native monomers. Chemical cross-linking or interaction with hsp70 increases the kinetic stability of fibrils and decreases their capacity to cause membrane disruption and cellular dysfunction. The results demonstrate how pH can modulate the deleterious effects of preformed amyloid aggregates and suggest why endocytic trafficking through acidic compartments may be a key factor in amyloid disease.

Original languageEnglish
Pages (from-to)5691-5696
Number of pages6
Journal Proceedings of the National Academy of Sciences of the United States of America
Issue number18
Publication statusPublished - 5 May 2015
Externally publishedYes


  • amyloid
  • fibrils
  • disassembly
  • oligomer
  • membrane disruption


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