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

Dániel Horváth, Zsolt Dürvanger, Dóra K. Menyhárd, Máté Sulyok-Eiler, Fruzsina Bencs, Gergő Gyulai, Péter Horváth, Nóra Taricska and András Perczel ()
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Dániel Horváth: ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University
Zsolt Dürvanger: ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University
Dóra K. Menyhárd: ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University
Máté Sulyok-Eiler: Laboratory of Structural Chemistry and Biology ELTE Eötvös Loránd University
Fruzsina Bencs: Laboratory of Structural Chemistry and Biology ELTE Eötvös Loránd University
Gergő Gyulai: Laboratory of Interfaces and Nanostructures, Institute of Chemistry, Eötvös Loránd University
Péter Horváth: Department of Pharmaceutical Chemistry, Semmelweis University
Nóra Taricska: ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University
András Perczel: ELKH-ELTE Protein Modeling Research Group ELTE Eötvös Loránd University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40294-x

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