8ANL

Structure of the amyloid-forming peptide LFIEWL from exendin-4, grown from water

Summary for 8ANL

• Entry DOI: 10.2210/pdb8anl/pdb
• Descriptor: Peptide LFIEWL from exendin-4 (2 entities in total)
• Functional Keywords: amyloid, protein fibril
• Biological source: Heloderma suspectum
• Total number of polymer chains: 4
• Total formula weight: 3279.94

Authors

Durvanger, Z. (deposition date: 2022-08-05, release date: 2023-08-02, Last modification date: 2024-06-19)

Primary citation

Horvath, D.,Durvanger, Z.,K Menyhard, D.,Sulyok-Eiler, M.,Bencs, F.,Gyulai, G.,Horvath, P.,Taricska, N.,Perczel, A.
Polymorphic amyloid nanostructures of hormone peptides involved in glucose homeostasis display reversible amyloid formation.
Nat Commun, 14:4621-4621, 2023

PubMed 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.

PubMed: 37528104
DOI: 10.1038/s41467-023-40294-x

Experimental method

X-RAY DIFFRACTION (1.75 Å)