Misfolding and aggregation of homo-amyloid peptides into small oligomers and large amyloid fibrils is believed to be responsible for the pathogenesis of many neurodegenerative diseases. More importantly and interestingly, different amyloid peptides can also cross-interact with each other to form hybrid amyloids. This important finding implies a potential functional link between different amyloid diseases, but little is known about the cross-sequence interactions and cross-seeding structures between different amyloid peptides. Here, using an in-house multiscale computational framework, we modeled and simulated different heteroassemblies formed by human islet amyloid polypeptide (hIAPP or amylin) and rat IAPP peptides. Simulations showed that the U-shaped hIAPP peptides can interact with conformationally similar rIAPP to form stable complexes and to co-assemble into heterogeneous structures, where hIAPP and rIAPP can elongate in the direction of the fibril axis and associate in the lateral direction. Stable hetero-interactions between hIAPP and rIAPP were shown to arise from hydrophobic contacts and hydrogen bonds at the interface, particularly at N- and C-terminal β-sheet regions. More importantly, rIAPP peptides could adopt different conformations and follow different pathways for associating with hIAPP from the high-energy of the bound state to the low-energy of the unbound state, without encountering any large and abrupt energy barrier. In parallel, ThT and AFM study of cross-aggregation of hIAPP and rIAPP provided additional evidence that hIAPP can seed with rIAPP to form hybrid fibrils at all concentrations similar to pure hIAPP fibrils. This work demonstrates the existence of cross-interactions between the two different IAPP peptides, which provides an improved fundamental understanding of the cross-seeding of different amyloid sequences towards amyloid aggregation and toxicity mechanisms.

Structural and energetic insight into the cross-seeding amyloid assemblies of human IAPP and rat IAPP

249th National Meeting (2015)

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