Structural characterization of amyloid fibrils from the human parathyroid hormone.

ABSTRACT

Amyloid deposits are common in various tissues as a consequence of misfolded proteins. However, secretory protein and peptides are often stored in membrane coated granules as functional amyloids. In this article, we present a detailed characterization of in vitro generated amyloid fibrils from human parathyroid hormone (hPTH(1-84)). Fully mature fibrils could be obtained after a short lag phase within less than one hour at 65°C. These fibrils showed all characteristic of a cross-ß structure. Protease cleavage combined with mass spectrometry identified the central region of the peptide hormone involved in the fibril core formation. EGCG, an inhibitor of amyloid fibril formation, showed binding to residues in the peptide monomers corresponding to the later fibril core and thus explaining the inhibition of the fibril growth. Conformational and dynamic studies by solid-state NMR further corroborated the cross-ß core of the fibrils, but also identified highly mobile segments with a random coil structure not belonging to the rigid fibril core.