Mapping out the multistage fibrillation of glucagon

Shirin Ghodke, Søren B Nielsen, Gunna Christiansen, Hans Aage Hjuler, James Flink, Daniel Otzen, Søren Bang Nielsen

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review


The 29-residue peptide hormone glucagon forms many different morphological types of amyloid-like fibrils, depending on solvent conditions. Here, we combine time-series far-UV CD with singular value decomposition analysis to reveal six different conformational states populated during fibrillation at 25 °C and pH 2.5. The existence of these states is supported by complementary fluorescence and electron microscopy data. This highlights a multitude of structural transitions of glucagon from unordered structure to β sheets, β turns and further tertiary-level changes. We attribute the observed unusual far-UV CD spectra to tertiary-level structural changes during the formation and maturation of fibrils. The fibrillation model for the whole process involves the formation of three oligomeric species and two different morphologies of fibrils in the same solution. The visualization of annular pore-like species in the early stages of glucagon fibrillation and the prevalence of such species in the amyloidogenesis of several proteins indicates that they may be a common feature of the fibrillation process. This study gives significant insights into the stepwise conversion of soluble glucagon to its fibrillar state and identifies the importance of fibril twisting for its thermodynamic stabilization. Structured digital abstract •  Glucagon and Glucagon bind by circular dichroism (View interaction) •  Glucagon and Glucagon bind by transmission electron microscopy (View interaction) •  Glucagon and Glucagon bind by fluorescence technology (View interaction).
TidsskriftF E B S Journal
Sider (fra-til)752-765
Antal sider13
StatusUdgivet - mar. 2012


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