The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations
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 therefo...
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/125383 |
| _version_ | 1811070162483281920 |
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| author | Gelenter, Martin David Liao, Shu-Yu Mandala, Venkata Shiva Dregni, Aurelio J. Hong, Mei |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Gelenter, Martin David Liao, Shu-Yu Mandala, Venkata Shiva Dregni, Aurelio J. Hong, Mei |
| author_sort | Gelenter, Martin David |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T08:28:59Z |
| format | Article |
| id | mit-1721.1/125383 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:28:59Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1253832022-09-23T12:43:19Z The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations Gelenter, Martin David Liao, Shu-Yu Mandala, Venkata Shiva Dregni, Aurelio J. Hong, Mei Massachusetts Institute of Technology. Department of Chemistry 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. National Institutes of Health (U.S.) (Grant AG059661) National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (1F31AI133989) 2020-05-21T17:45:09Z 2020-05-21T17:45:09Z 2019-07 2020-01-17T17:46:08Z Article http://purl.org/eprint/type/JournalArticle 1545-9993 https://hdl.handle.net/1721.1/125383 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) en 10.1038/s41594-019-0238-6 Nature structural & molecular biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Gelenter, Martin David Liao, Shu-Yu Mandala, Venkata Shiva Dregni, Aurelio J. Hong, Mei The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations |
| title | The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations |
| title_full | The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations |
| title_fullStr | The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations |
| title_full_unstemmed | The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations |
| title_short | The peptide hormone glucagon forms amyloid fibrils with two coexisting β-strand conformations |
| title_sort | peptide hormone glucagon forms amyloid fibrils with two coexisting β strand conformations |
| url | https://hdl.handle.net/1721.1/125383 |
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