Abstract
Glucagon is a 29-residue amphiphatic hormone involved in the regulation of blood glucoselevels in conjunction with insulin. In concentrated aqueous solutions, glucagonspontaneously aggregates to form amyloid fibrils, destroying its biological activity. In thisstudy we utilize the atomic force microscope (AFM) to elucidate the fibrillationmechanism of glucagon at the nanoscale under acidic conditions (pH 2.0) by visualizingthe nanostructures of fibrils formed at different stages of the incubation. Hollowdisc-shaped oligomers form at an early stage in the process and subsequently rearrangeto more solid oligomers. These oligomers co-exist with, and most likely act asprecursors for, protofibrils, which subsequently associate to form at least threedifferent classes of higher-order fibrils of different heights. A repeat unit of around50 nm along the main fibril axis suggests a helical arrangement of interwovenprotofibrils. The diversity of oligomeric and fibrillar arrangements formed at pH 2.0complements previous spectroscopic analyses that revealed that fibrils formed underdifferent conditions can differ substantially in stability and secondary structure.
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