AFM study of glucagon fibrillation via oligomeric structures resulting in interwoven fibrils

Nanotechnology. 2006 Aug 28;17(16):4003-9. doi: 10.1088/0957-4484/17/16/001. Epub 2006 Jul 14.

Abstract

Glucagon is a 29-residue amphiphatic hormone involved in the regulation of blood glucose levels in conjunction with insulin. In concentrated aqueous solutions, glucagon spontaneously aggregates to form amyloid fibrils, destroying its biological activity. In this study we utilize the atomic force microscope (AFM) to elucidate the fibrillation mechanism of glucagon at the nanoscale under acidic conditions (pH 2.0) by visualizing the nanostructures of fibrils formed at different stages of the incubation. Hollow disc-shaped oligomers form at an early stage in the process and subsequently rearrange to more solid oligomers. These oligomers co-exist with, and most likely act as precursors for, protofibrils, which subsequently associate to form at least three different classes of higher-order fibrils of different heights. A repeat unit of around 50 nm along the main fibril axis suggests a helical arrangement of interwoven protofibrils. The diversity of oligomeric and fibrillar arrangements formed at pH 2.0 complements previous spectroscopic analyses that revealed that fibrils formed under different conditions can differ substantially in stability and secondary structure.