Polymorphism, metastable species and interconversion: the many states of glucagon fibrils

Research output: Research - peer-reviewBook chapter

  • Shirin D Ghodke
    Shirin D GhodkeDenmark
  • Grethe Vestergaard Jensen
    Grethe Vestergaard JensenDenmark
  • Anna Sigrid P. Svane
    Anna Sigrid P. SvaneDenmark
  • Katrin Weise
    Katrin WeiseUniversity of Dortmund, Department of Chemistry, Physical Chemistry I, DortmundGermany
  • Anne Søndergaard
    Anne SøndergaardDenmark
  • Manja Annette Behrens
    Manja Annette BehrensDenmark
  • Jan Skov Pedersen
  • Niels Christian Nielsen
  • Jesper Søndergaard Pedersen
    Jesper Søndergaard PedersenDet Teknisk-Naturvidenskabelige FakultetDenmark
  • Roland Winter
    Roland WinterUniversity of Dortmund, Department of Chemistry, Physical Chemistry I, DortmundGermany
  • Daniel Otzen
The natively unfolded peptide hormone glucagon forms fibrillar structures with amyloid properties. Here, we summarize past advances in glucagon fibrillation and combine them with recent new unpublished data to provide some more general conclusions on how glucagon fibrillation adapts to different physicochemical conditions such as high temperature, pressure, mechanical and chemical stress. Factors such as peptide concentration, accessible surface area, surface hydration of the glucagon molecular state, contact surface, temperature and ionic strength all contribute to fibrillar structure and stability. In addition to fundamental changes in secondary structure, glucagon fibril morphology can vary at two macroscopic levels, namely, the degree of association (three-filament fibrils form under quiescent conditions, and two-filament fibrils form with vigorous shaking) and the type of association (twisted fibrils at low temperature, rod-like bundled fibrils at higher temperatures). Laterally bundled fibrils are presumably more stable because of the larger effective contact area. Polymorphism also opens up for interconversion of different fibril types: the low temperature fibrils can convert to a more stable fibril upon incubation at elevated temperatures (but not vice versa), indicating that fibrils are fundamentally malleable if they have not attained the most stable fibrillar state. While the effect of pressure on glucagon is complex (accelerating fibrillation at intermediate pressures and decelerating it at higher pressures), the thermal expansion coefficients obtained from these studies agree well with our previous calorimetric studies to reveal reduced or increased hydration of fibrils (leading to reduced or increased stability) depending on fibrillation conditions. Finally, we report that the cyclodextrin kleptose retards glucagon fibrillation but without interfering fundamentally with the monomer–oligomer equilibrium.
Original languageEnglish
Title of host publicationBio-nanoimaging: Protein misfolding and aggregation
EditorsVladimir Uversky, Yuri Lyubchenko
Number of pages14
PublisherElsevier Science
Publication year2014
Pages373-386
Chapter34
ISBN (print)978-0-12-394431-3
DOIs
StatePublished - 2014

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