Atomistic structure of the interlocking claw-like amyloid fibril of full-length glucagon
Glucagon is a peptide hormone which posits a significant potential as a therapeutic molecule for various human diseases. One of the major challenges hampering medicinal application of glucagon, however, is its insoluble and aggregation-prone property. Although glucagon is dissolvable, it aggregates easily and forms amyloid fibrils. To date, despite many studies to understand how glucagon aggregates and fibrillizes, its detailed amyloidogenesis mechanism is still elusive, particularly due to insufficient structural information of glucagon amyloid fibrils. Here we report the novel structure of a glucagon amyloid fibril, which was determined with cryo-electron microscopy (cryo-EM) to a 3.8-[A] resolution. Our model features with tight and extensive inter-monomer interactions, which efficiently stabilize the entire chain of full-length glucagon into the V-shape conformation, clamping the other monomer to construct a dimeric architecture orthogonal to the fibril axis. Notably, the current structure significantly differs from the previous solid-state NMR model, which gives direct evidence for multiple and dynamic amyloidogenesis mechanisms of glucagon. In addition, our results are expected to provide important insights to appreciate the molecular details of glucagon in its initial amyloidogenesis and fibril elongation processes.