Domain swapping as a molecular mechanism in amyloidosis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

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.

Details

Authors
  • Maria Wahlbom
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • 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
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2007 Nov 24
Publisher
  • Department of Clinical and Experimental Pharmacology, Lund University
Print ISBNs978-91-85897-29-2
Publication statusPublished - 2007
Publication categoryResearch

Bibliographic note

Defence details Date: 2007-11-24 Time: 09:00 Place: Segerfalkssalen, Wallenberg Neurocenter, Sölvegatan 17. Lund External reviewer(s) Name: Theodorsson, Elvar Title: Professor Affiliation: IBK/Klinisk kemi, Universitetssjukhuset, 58185 Linköping ---

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Related research output

Maria Wahlbom, Xin Wang, Veronica Lindström, Eric Carlemalm, Mariusz Jaskolski & Anders Grubb, 2007, In: Journal of Biological Chemistry. 282, 25, p. 18318-18326

Research output: Contribution to journalArticle

Maria Wahlbom, Xin Wang, Sylwia Rodziewicz-Motowidlo, Robert Janowski, Veronica Lindström, Patrik Önnerfjord, Gunilla Westermark, Zbigniew Grzonka, Mariusz Jaskolski & Anders Grubb, 2004, In: Journal of Biological Chemistry. 279, 23, p. 24236-24245 10 p.

Research output: Contribution to journalArticle

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