La región intrínsecamente desordenada de la hormona paratiroidea humana controla las propiedades amiloides...

Human parathyroid hormone (PTH), which regulates the calcium and phosphate level 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 35-84 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 extend 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 towards the physiological requirement of monomer release after cellular storage.