Amylin (also known as islet amyloid polypeptide) forms amyloid in the islets of Langerhans in type-2 diabetes, a process which contributes to β-cell dysfunction and death. The feature which controls the amyloidogenicity of amylin and the mechanism of amyloid formation is not fully understood. Not all species form islet amyloid and its presence or absence correlates with the in vitro behavior of the polypeptide. Rats and mice do not develop type-2 diabetes or islet amyloid and rat/mouse amylin is non-amyloidogenic, except at very high concentrations. The only rodent which has been reported to develop islet amyloid in vivo is the Degu, however, the amyloid deposits are comprised of insulin. This has led to the system that rodent amylins are non-amyloidogenic. Prairie vole amylin has an unusual sequence compared to both human and rat/mouse amylin including a non-conservative Lys to Glu substitution. Prairie vole amylin also contains only one Pro compared to three in rat/mouse amylin. The role of the N-terminus region of amylin in amyloid formation is largely unexplored and no analysis of N-terminal mutants has been reported. Prairie vole amylin does form, albeit 5-fold more slowly than human amylin in vitro in PBS buffer and 9-fold more slowly in Tris buffer. The prairie vole peptide is considerably less cytotoxic than human amylin. The Lys to Glu substitution accounts for part of the reduction in toxicity and amyloidogenicity relative to human amylin, despite reducing the net charge of the polypeptide. The amyloid formation by the Glu-1 variant of human amylin is moderately slower in PBS, but faster than wild type in Tris. This effect likely reflects competing interactions: the K1E mutation of human amylin reduces the net charge on the peptide in the region at the highest charge density and this is likely to lead to fast aggregation. However, the rate of amyloid formation of amylin is known to depend on the type of the anion in solution and is also known to be faster in phosphate. Thus, in PBS the effect is believed to be due to the interaction of phosphate with human amylin. Reversal of the positive charge in the sidechain of residue-1 leads to weaker interactions between phosphate and human amylin.

Analysis of prairie vole amylin reveals the importance of the N-terminal residue of human amylin in amyloidogenicity and cytotoxicity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.