The Effects of Lipid Membranes, Crowding and Osmolytes on the Aggregation, and Fibrillation Propensity of Human IAPP

Figure 7

Suppressive effect of macromolecular crowding on hIAPP aggregation and cytotoxicity. (a) Schematic illustration of the excluded volume effect caused by different polymer and protein crowding agents (A: Ficoll and dextran, B: BSA, C: lysozyme). (b) Moderate to strong interaction between ratIAPP and the crowding agent at equimolar concentration, as analyzed from FCS measurements, affect the aggregation kinetics of 10 μM hIAPP differently as measured by ThT fluorescence spectroscopy (c, d). In addition, a crowder concentration dependent decrease of the fibril amount formed is observed. (e) The effect of macromolecular crowding favors the formation of nontoxic off-pathway hIAPP species. (f) In summary, with the results from complementary AFM and ATR-FTIR studies, two competing reaction pathways of hIAPP aggregation under crowding conditions are revealed. The horizontal path shows the well-known hIAPP aggregation mechanism from a natural monomeric disordered structure via formation of nuclei and oligomers to fibril accumulation. The competing crowder type dependent stabilization of nontoxic, off-pathway and globular hIAPP species is shown in a vertical path. Adapted and modified from [151].

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