Polymorphic amyloid nanostructures of hormone peptides involved in glucose homeostasis display reversible amyloid formation
In this work, the authors highlight that 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 fibr
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. The authors determine nine polymorphic crystal structures of the APR segments of glucagon-like peptides 1 and 2, and exendin and its derivatives. Amyloid formation is characterized by CD, FTIR, ThT assays, and AFM. pH sensitivity is proposed to 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. Reversible amyloid formation of hormone peptides has implications for understanding the complex regulation of glucose homeostasis in the body. The results also suggest that the dual nature of conserved receptor binding segments may play a crucial role in the pH-dependent conversion between amyloid and functional forms of these hormones.