Association of Highly Compact Type II Diabetes Related Islet Amyloid Polypeptide Intermediate Species at Physiological Temperature Revealed by Diffusion NMR Spectroscopy

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Abstract

Self-association of human islet amyloid polypeptide (hIAPP) is correlated with the development of type II diabetes by the disruption of cellular homeostasis in islet cells through the formation of membrane-active oligomers. The toxic species of hIAPP responsible for membrane damage has not been identified. In this study, we show by pulsed field gradient NMR spectroscopy that the monomeric form of the toxic, amyloidogenic human variant of IAPP (hIAPP) adopts a temperature dependent compact folded conformation that is absent in both the nontoxic and nonamyloidogenic rat variant of IAPP and absent in hIAPP at low temperatures, suggesting this compact form of monomeric hIAPP may be linked to its later aggregation and cytotoxicity. In addition to the monomeric form of hIAPP, a large oligomeric species greater than 100 nm in diameter is also present but does not trigger the nucleation-dependent aggregation of IAPP at 4 degrees C, indicating the large oligomeric species may be an off-pathway intermediate that has been predicted by kinetic models of IAPP fiber formation. Furthermore, analysis of the polydispersity of the calculated diffusion values indicates small oligomeric species of hIAPP are absent in agreement with a recent ultracentrifugation study. The absence of small oligomeric species in solution suggests the formation of small, well-defined ion channels by hIAPP may proceed by aggregation of monomeric IAPP on the membrane, rather than by the insertion of preformed structured oligomers from the solution state as has been proposed for other amyloidogenic proteins.

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