Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping.

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Abstract

Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu(68)-> Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize faster and at a lower concentration than the monomeric protein, indicating a role of the oligomers as fibril-assembly intermediates. Moreover, the present work demonstrates that three-dimensional domain swapping is involved in the formation of the oligomers, because variants of monomeric cystatin C, stabilized against three-dimensional domain swapping by engineered disulfide bonds, do not produce oligomers upon incubation under non-reducing conditions. Redox experiments using wild type and stabilized cystatin C strongly suggest that the oligomers, and thus probably the fibrils as well, are formed by propagated domain swapping rather than by assembly of domain-swapped cystatin C dimers.

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Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
  • Radiology, Nuclear Medicine and Medical Imaging
  • Pharmacology and Toxicology
Original languageEnglish
Pages (from-to)18318-18326
JournalJournal of Biological Chemistry
Volume282
Issue number25
StatePublished - 2007
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Electron Microscopy Unit (013100002), Division of Clinical Chemistry and Pharmacology (013250300)

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Wahlbom, M., 2007, Department of Clinical and Experimental Pharmacology, Lund University. 92 p.

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