The intrinsically disordered region of the human parathyroid hormone controls functional amyloid properties

Human parathyroid hormone (PTH), which regulates the calcium and phosphate levels in blood, forms functional amyloid fibrils, which are believed to be the storage form during secretion from parathyroid glands. We investigated by various biophysical approaches the role of the intrinsically disordered C-terminal section 35 to 84 of the peptide hormone, which is conserved in mammals but not required for activation of the target G protein-coupled PTH receptors. The flanking intrinsically disordered region (IDR) of PTH, which is not part of the cross-β fibrillar core structure, impairs the lateral filament order and reduces the thermodynamic stability to an extent that monomer release from the fibrils reaches a physiological level. Concentration-dependent fibrillation kinetics revealed that the IDR increases the critical fibrillation and oligomer concentration and screens secondary nucleation. We propose that the IDRs of PTH shape the generic property of the hormone to form amyloid fibrils toward the physiological requirement of monomer release after cellular storage.