Polymorphic Amyloid Nanostructures of Hormone Peptides Involved in Glucose Homeostasis Display Reversible Amyloid Formation
Conserved receptor binding segments of class B GPCR ligands have a dual nature: they serve as amyloid-prone regions involved in pH-dependent conversion from secretory amyloid fibrils to the functional folded form.
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. Here, researchers identify an evolutionarily conserved hexapeptide sequence as the major aggregation-prone region (APR) of gastrointestinal peptides of the glucagon family: xFxxWL. They determine nine polymorphic crystal structures of the APR segments of glucagon-like peptides 1 and 2, and exendin and its derivatives. The researchers follow amyloid formation by CD, FTIR, ThT assays, and AFM. They propose that the pH-dependent changes of the protonation states of glutamate/aspartate residues of APRs initiate switching between the amyloid and the folded, monomeric forms of the hormones. In the absence of acidic gatekeepers, pH sensitivity diminishes, and amyloid formation progresses over a broad pH range. The findings highlight the dual role of short aggregation core motifs in reversible amyloid formation and receptor binding, which have implications for understanding the complex regulation of hormone function and glucose homeostasis in the body.