Generation of Membrane-Damaging hIAPP Oligomers via Direct Interaction with DOPC/DOPS Nanodiscs

The amyloidogenesis of the pancreatic metabolic hormone human islet amyloid polypeptide (hIAPP) is associated with dysfunction of the pancreatic β-cell function in type II diabetes. Although the β-cell membrane is known to play a crucial role in amyloid formation of the hIAPP, the mechanistic understanding of this membrane-mediated process remains largely unclear. Here, using extensive biophysical and simulation experiments, we have investigated the direct interaction between the hIAPP with lipid nanodiscs mimicking the anionic β-cell membrane (7:3 DOPC/DOPS). Our data confirmed that nanodiscs significantly suppressed hIAPP fibrillation by stabilizing the oligomeric conformer. Importantly, these membrane-bound oligomers, rather than mature fibrils, are responsible for membrane disruption, as demonstrated by ³¹P solid-state NMR and dye leakage assays. Atomistic molecular dynamics (MD) simulations reveal that the initial adsorption is driven by the positively charged <i>N</i>-terminal residues (K1, N3, and R11) of the hIAPP. At acidic pH, representative of secretory granules, the central region (including His18) also contributes to membrane binding. These findings are quantitatively validated by residue-specific NMR chemical shift perturbations and relaxation measurements. Collectively, the result provides a mechanistic insight into how the β-cell membrane catalyzes the formation of toxic hIAPP oligomers, offering an improved therapeutic strategy against type II diabetes.