Polymorphic amyloid nanostructures of hormone peptides involved in glucose homeostasis display reversible amyloid formation

• Published in: Nature communications Vol. 14; no. 1; p. 4621
• Main Authors: Horváth, Dániel, Dürvanger, Zsolt, K. Menyhárd, Dóra, Sulyok-Eiler, Máté, Bencs, Fruzsina, Gyulai, Gergő, Horváth, Péter, Taricska, Nóra, Perczel, András
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 147/3; 631/337/470/2284; 631/45/611; 631/45/776/1178; 631/535/1266; Amyloid - metabolism; Amyloidogenic Proteins; Binding; Conserved sequence; Fibrils; G protein-coupled receptors; Glucagon; Glucose; Homeostasis; Hormones; Humanities and Social Sciences; multidisciplinary; Nanostructures - chemistry; Peptides; Peptides - chemistry; pH effects; Protonation; Receptors; Science; Science (multidisciplinary); Segments
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40294-x

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, we identify an evolutionarily conserved hexapeptide sequence as the major aggregation-prone region (APR) of gastrointestinal peptides of the glucagon family: xFxxWL. We determine nine polymorphic crystal structures of the APR segments of glucagon-like peptides 1 and 2, and exendin and its derivatives. We follow amyloid formation by CD, FTIR, ThT assays, and AFM. We 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. We find that pH sensitivity diminishes in the absence of acidic gatekeepers and amyloid formation progresses over a broad pH range. Our results highlight the dual role of short aggregation core motifs in reversible amyloid formation and receptor binding. 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 fibrils to the functional folded form.