Human Islet amyloid polypeptide (hIAPP) is a 37-residue hormone polypeptide whose misfolding and aggregation into amyloid fibrils are tightly associated with type II diabetes. While rat islet amyloid polypeptide (rIAPP), which differs in 6 of the 37 residues, does not develop amyloid fibrils and induce toxicity to islet �-cells. Due to the high degree of sequence similarity and nontoxic nature of rIAPP, rIAPP is often considered as a native inhibitor to prevent hIAPP aggregation and toxicity. However, inhibition role of rIAPP is still hotly debated with many contradicting data in literature. To address this issue, here we study the effect of cross-sequence interaction between hIAPP and rIAPP peptides on hybrid amyloid structures, aggregation kinetics, and cell toxicity using combined biophysics experiment (ThT, AFM, and cell viability assay) and molecular dynamic (MD) simulations. Experimental results show that rIAPP indeed exerts the inhibition effect on hIAPP aggregation at the very early stage, but once hIAPP forms the template seeds with cross-� structures, which in turn recruit rIAPP to be associated with them and to grow into hybrid amyloid fibrils similar to hIAPP fibrils. More importantly, the cross-sequence interactions induce the greater toxicity to cells, suggesting that rIAPP can be grown onto hIAPP seeds to produce more toxic species. MD simulations further confirm that cross-seeding interactions enable to stabilize the hybrid hIAPP-rIAPP oligomers with a �-strand�turn-�-strand structure, as explained by our selective molecular recognition mechanism. These findings provide unprecedented insights into the seed selection between hIAPP and rIAPP and establish conformational compatibility as an important driving force in amyloid fibril propagation.

Effects of cross-sequence interaction between human and rat islet amyloid polypeptides on the structure, aggregation, and toxicity of zmyloids

247th National Meeting (2014)

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