The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations
Name
nihms-1528216.pdf
Description
Accepted version
Size
1.7 MB
Format
Adobe PDF
Checksum (MD5)
1f7d2bab5180c4117cf87fee4e9ffe25
Author(s)
Gelenter, Martin David
Liao, Shu-Yu
Mandala, Venkata Shiva
Dregni, Aurelio J.
Hong, Mei
Date Issued
July 2019
Journal
Nature structural & molecular biology
Publisher
Springer Science and Business Media LLC
Citation
Gelenter, Martin D. et al. “The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations.” Nature structural & molecular biology 26 (2019): 592-598 © 2019 The Author(s)
Version
Author's final manuscript
Abstract
Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia, respectively, in patients with diabetes. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility and is therefore formulated as a lyophilized powder that is reconstituted in an acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown at pharmaceutically relevant low pH. Unexpectedly, two sets of chemical shifts are observed, indicating the coexistence of two β-strand conformations. The two conformations have distinct water accessibilities and intermolecular contacts, indicating that they alternate and hydrogen bond in an antiparallel fashion along the fibril axis. Two antiparallel β-sheets assemble with symmetric homodimer cross sections. This amyloid structure is stabilized by numerous aromatic, cation-π, polar and hydrophobic interactions, suggesting mutagenesis approaches to inhibit fibrillization could improve this important drug.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41594-019-0238-6
