Yang, T. and Filippov, I. and Manathunga, L. and Baghai, A. and Marechal, Amandine and Raleigh, D.P. and Zhyvoloup, A. (2024) On the importance of being amidated: analysis of the role of the conserved C-terminal amide of amylin in amyloid formation and cytotoxicity. Biophysical Chemistry 307 (107168), ISSN 0301-4622.
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Abstract
The polypeptide hormone Amylin (also known as islet amyloid polypeptide) plays a role in regulation of glucose metabolism, but forms pancreatic islet amyloid deposits in type 2 diabetes. The process of islet amyloid formation contributes to β-cell dysfunction and the development of the disease. Amylin is produced as a pro-from and undergoes processing prior to secretion. The mature hormone contains an amidated C-terminus. Analysis of an alignment of vertebrate amylin sequences reveals that the processing signal for amidation is strictly conserved. Furthermore, the enzyme responsible for C-terminal amidation is found in all of these organisms. Comparison of the physiologically relevant amidated form to a variant with a free C-terminus (Amylin-COO-) shows that replacement of the C-terminal amide with a carboxylate slows, but does not prevent amyloid formation. Pre-fibrillar species produced by both variants are toxic to cultured β-cells, although hAmylin-COO- is moderately less so. Amyloid fibrils produced by either peptide are not toxic. Prior work (ACS Pharmacol. Translational. Sci. 1, 132–49 (2018)) shows that Amylin- COO- exhibits a 58-fold reduction in activation of the Amylin1 receptor and 20-fold reduction in activation of the Amylin3 receptor. Thus, hAmylin-COO- exhibits significant toxicity, but significantly reduced activity and offers a reagent for studies which aim to decouple hAmylin’s toxic effects from its activity. The different behaviours of free and c-terminal amidated Amylin should be considered when designing systems to produce the polypeptide recombinantly.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Amandine Marechal |
| Date Deposited: | 11 Mar 2024 14:28 |
| Last Modified: | 12 Mar 2024 07:29 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/53210 |
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