Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a number of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the molecular mechanisms underlying these events are unknown. Using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide associated with β-cell death in type 2 diabetes, we demonstrate that the presence of Ca(2+) ions inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, atomic force microscopy, and NMR experiments show that Ca(2+) ions promote a shallow membrane insertion of hIAPP, which leads to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity.

The aggregation of human islet amyloid polypeptide (hIAPP) has been linked to beta-cell death in type II diabetes. Zinc present in secretory granules has been shown to affect this aggregation. A combination of EXAFS, NMR, and AFM experiments shows that the influence of zinc is most likely due to the stabilization of prefibrillar aggregates of hIAPP.

Protein adsorption plays a key role in the biological response to implants. We report how nanoscale topography, chemistry, crystallinity, and molecular chain anisotropy of ultrahigh molecular weight polyethylene (UHMWPE) surfaces affect the protein assembly and induce lateral orientational order. We applied ultraflat, melt drawn UHMWPE films to show that highly oriented nanocrystalline lamellae influence the conformation and aggregation into network structures of human plasma fibrinogen by atomic force microscopy with unprecedented clarity and molecular resolution. We observed a transition from random protein orientation at low concentrations to an assembly guided by the UHMWPE surface nanotopography at a close to full surface coverage on hydrophobic melt drawn UHMWPE. This assembly differs from the arrangement at a hydrophobic, on the nanoscale smooth UHMWPE reference. On plasma-modified, hydrophilic melt drawn UHMWPE surfaces that retained their original nanotopography, the influence of the nanoscale surface pattern on the protein adsorption is lost. A model based on protein-surface and protein-protein interactions is proposed. We suggest these nanostructured polymer films to be versatile model surfaces to provide unique information on protein interactions with nanoscale building blocks of implants, such as nanocrystalline UHMWPE lamellae. The current study contributes to the understanding of molecular processes at polymer biointerfaces and may support their future design and molecular scale tailoring.

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