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Domain swapping as a molecular mechanism in amyloidosis

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Author

  • Maria Wahlbom

Summary, in English

Amyloidosis is a group of diseases characterized by a change in protein conformation resulting in aggregation and tissue deposition of amyloid fibrils. One variant of cystatin C, L68Q cystatin C, is highly amyloidogenic and persons carrying the corresponding gene suffer from massive cerebral amyloidosis leading to brain hemorrhage and death. Amyloidogenic proteins like cystatin C and prion proteins have been shown to form dimers by exchange of subdomains of the monomeric proteins. This process, called ?domain swapping?, has also been suggested to play a part in the generation of amyloid fibrils. In the present work the role of this mechanism is investigated. Two variants of wild type and L68Q cystatin C, respectively, with disulfide bonds at positions selected to inhibit domain swapping have been produced. It was observed that the capacity of the four proteins to form dimers, oligomers and fibrils was prevented, implying an important role of ?domain swapping? in the aggregation process. Oligomers of cystatin C were detected already in the beginning of the lag phase of the fibrillization reaction. The appearance of these doughnut-shaped oligomers is similar to that described for oligomers of other amyloidogenic proteins. Purified oligomers of cystatin C were shown to fibrillize faster and at a lower concentration than the monomeric protein, suggesting a role of the oligomers as fibril-assembly intermediates. Furthermore, high molecular weight cystatin C immunoreactive components were detected in samples obtained from mice, expressing human L68Q cystatin C, while no such species could be observed in control mice.

Publishing year

2007

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2007:151

Document type

Dissertation

Publisher

Department of Clinical and Experimental Pharmacology, Lund University

Topic

  • Medicinal Chemistry
  • Pharmacology and Toxicology

Keywords

  • Clinical chemistry
  • Klinisk kemi
  • Medicin (människa och djur)
  • Medicine (human and vertebrates)
  • oligomer
  • dimer
  • domain swapping
  • fibril
  • cystatin C
  • amyloidosis

Status

Published

Supervisor

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-85897-29-2

Defence date

24 November 2007

Defence time

09:00

Defence place

Segerfalkssalen, Wallenberg Neurocenter, Sölvegatan 17. Lund

Opponent

  • Elvar Theodorsson (Professor)