![]() ![]() Each of the β-strands forms an intermolecular parallel β-sheet pairing with the equivalent β-strand from an adjacent amylin monomer. The consensus from these studies is that the amylin monomers adopt a hairpin structure composed of two β-strands in the fibrils. The structure of amylin fibrils has been characterized by solid-state nuclear magnetic resonance (ssNMR), electron paramagnetic resonance (EPR), two-dimensional infrared spectroscopy (2DIR) and cryo-electron microscopy (cryo-EM). Even if fibrils are not the main culprits, their properties are important to understand since they could serve as a reservoir from which toxic oligomers dissociate. As with other amyloid diseases it is unclear whether fibrils or soluble oligomers are responsible for amylin pathology –. The amyloid plaques have been implicated in the destruction of pancreatic β-cells that synthesize both amylin and insulin. One of the hallmarks of advanced type 2 diabetes is the development of amyloid plaques consisting of the endocrine hormone amylin (also known as islet amyloid polypeptide or IAPP). Insulin resistance and high blood glucose levels characterize the disease but its causes are multi-factorial. Type 2 diabetes affects over 300 million people worldwide, with the incidence of the disease expected to reach over 500 million by 2030. Differences in protection appear to be due to restrictions on backbone dynamics imposed by the packing of two-layers of C2-symmetry-related β-hairpins in the protofilament structure, with strand β1 positioned on the surface and β2 in the interior. ![]() There is variation in protection within the β-strands, particularly for strand β1 where only residues F15-H18 are strongly protected. Based on the protection data we conclude that residues A8-H18 and I26-Y37 comprise the two β-strands in amylin fibrils. Hydrogen exchange lifetimes at pH 7.6 and 37☌ vary between ∼5 h for the unstructured N-terminus to 600 h for amide protons in the two β-strands that form inter-molecular hydrogen bonds between amylin monomers along the length of the fibril. In this technique, partially exchanged fibrils are dissolved in 95% DMSO and information about amide proton occupancy in the fibrils is determined from DMSO-denatured monomers. ![]() To better characterize the secondary structure of amylin in amyloid fibrils we assigned the NMR spectrum of the unfolded state in 95% DMSO and used a quenched hydrogen-deuterium exchange technique to look at amide proton solvent protection in the fibrils. The amyloid plaques have been implicated in the destruction of pancreatic β-cells, which synthesize amylin and insulin. ![]()
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