Polymorphic Amyloid Nanostructures of Hormone Peptides Involved in Glucose Homeostasis Display Reversible Amyloid Formation

A large group of hormones are stored as amyloid fibrils in acidic secretion vesicles before they are released into the bloodstream and readopt their functional state. This process is mediated by conserved receptor binding segments of class B GPCR ligands, which exhibit a dual nature: they serve as amyloid-prone regions involved in pH-dependent conversion from secretory amyloid fibrils to the functional folded form. In this context, researchers have identified an evolutionarily conserved hexapeptide sequence, xFxxWL, as the major aggregation-prone region (APR) of gastrointestinal peptides of the glucagon family. The structure and dynamics of this region have been elucidated through high-resolution crystallography, which reveals a complex interplay between pH-dependent protonation states and the formation of amyloid nanostructures. Furthermore, the absence of acidic gatekeepers is found to diminish pH sensitivity, leading to progressive amyloid formation over a broad pH range. The authors' findings underscore the importance of short aggregation core motifs in reversible amyloid formation and receptor binding, highlighting a critical mechanism underlying glucose homeostasis.