Analysis of Prairie Vole Amylin Reveals the Importance of the N-terminus and Residue-22 in Amyloidogenicity and Cytotoxicity

Amyloid formation by amylin contributes to β-cell dysfunction in type-2 diabetes. The features which control the amyloidogenicity and toxicity of amylin are not understood. Not all species form islet amyloid and its presence or absence correlates with the in vitro behavior of the polypeptide. Rats do not develop type-2 diabetes or islet amyloid and rat amylin is non-amyloidogenic, except at very high concentrations. This has led to the notion that rodent amylins are non-amyloidogenic. Prairie vole amylin has an unusual sequence compared to human and rat amylin, including non-conservative Lys-1 to Glu and Asn-22 to Gly substitutions. The first reduces the net charge on the peptide, while the second disrupts a potential network of sidechain hydrogen bonds in the amyloid fiber, a so called Asn ladder. The prairie vole polypeptide forms amyloid more slowly than human amylin and is considerably less cytotoxic. An Asn-22 to Gly substitution in human amylin significantly reduces toxicity, increasing the effectiv...