Structural Insights into the Polymorphism of Self‐Assembled Amylin Oligomers

Abstract

Type 2 diabetes (T2D) affects over 300 million people worldwide. The main component, found in the pancreas of 95 % of T2D patients, is amylin oligomers and fibrils. So far, four different molecular structures of the self‐assembled amylin oligomers have been observed experimentally: two ssNMR models and two crystal models. This review illustrates that there are further self‐assembled amylin oligomers that differ in the orientations of the side chains along the β‐arch and are all derived from the two ssNMR models. This review focuses on polymorphism of the self‐assembled amylin oligomers. It also provides the various pathway mechanisms which lead to various amylin oligomers. Finally, it illustrates that interactions of amylin oligomers with further amyloids, such as Aβ oligomers, increase the polymorphism by forming polymorphic states of amylin‐Aβ oligomers with various pathway mechanisms. The polymorphism of amylin oligomers and the polymorphism of the cross‐seeding amylin‐Aβ oligomers phenomena could contribute to explaining, at least in part, the still unknown origins of the pathological conditions, and may assist in preventing aggregation in amyloidogenic diseases with drug design and other therapeutic approaches.

Membrane Interactions of hIAPP Monomer and Oligomer with Lipid Membranes by Molecular Dynamics Simulations

“…To distinguish these four experimentally proposed models of hIAPP, Miller and co-workers proposed to use different experimentally hIAPP models as structural templates to reassemble them into new fibril-like structures (M1-M4 models). In this work, hIAPP pentamer, used as in our previous studies, − was computationally constructed from the Tycko double-layer model, which was similar to the M2 model in Miller’s work. − We note that different hIAPP models even with subtle side chain variations may or may not alter the membrane interactions of hIAPP oligomers to some extent, which will require additional work to explore in the future. hIAPP pentamer was constructed by stacking five hIAPP monomers together in the in-register manner with the interpeptide distance of 4.7 Å.…”

A new polymorphism of human amylin fibrils with similar protofilaments and a conserved core

“… 4 , 5 , 6 However, under chronic hyperglycemic conditions associated with type 2 diabetes (T2D), overexpressed hIAPP aggregates into polymorphic protofilament forms, which can recruit and convert native hIAPP monomers into consistent or different fibril states to form amyloid deposits. 7 , 8 Aggregated hIAPP has been identified as a toxicant associated with the dysfunction and death of beta-cells, and found in over 95% of individuals with T2D. 4 , 9 , 10 , 11 , 12 The amyloidosis process of hIAPP and its toxicity are still not well understood.…”