LAUSR

Functional amyloids belong to an increasing class of non-toxic biologic material, in contrast to the prominent disease-related amyloids. Here, we report on the fibril formation of the parathyroid hormone PTH84 as a representative candidate following the same generic principles of primary and secondary nucleation. Employing Thioflavin T monitored kinetics analyses and negative-staining transmission electron microscopy we found an intricate, concentration dependent behavior of time dependent generation and morphologies of PTH84 fibrils. While at low peptide concentrations, fibril formation is driven by surface catalyzed secondary nucleation, an increased amount of peptides cause a negative feedback on fibril elongation and secondary nucleation. Moreover, the source of primary nuclei was found to regulate the overall macroscopic fibrillation. As a consequence, the concentration dependent competition of primary versus secondary nucleation pathways was found to dominate the mechanism of fibril generation. We are able to hypothesize an underlying monomer-oligomer equilibrium providing high-order species for primary nucleation and, additionally, negatively affecting the available monomer pool. This article is protected by copyright. All rights reserved.