Molecular Mechanisms of Protein–Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer’s

Abstract

The disruption of cell membranes by tau and amylin oligomers is linked to amyloid diseases such as Alzheimer’s and diabetes, respectively. The recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-oligomers that are structurally different from homo-oligomers. However, the molecular interactions of these hetero-oligomers with the neuronal membranes remain unclear. Using MD simulations, we have investigated the binding behaviors, membrane disruption, and protein folding of hetero-oligomers on a raft membrane containing phase-separated lipid nanodomains like those found in neurons. We discovered that the hetero-oligomers bind to the liquid-order and liquid-disorder phase boundaries of the raft membrane. The major lipid-binding sites of these interactions include the L16 and I26 residues of amylin and the N-terminal of tau. Strong disruptions of the raft domain size by the hetero-tetramer were detected. Furthermore, the hetero-dimer disrupted the saturated phospholipid orientational order to a greater extent than the individual tau or amylin monomer. In addition, the constituent tau more strongly promoted the alpha-helix to the beta-sheet transition of the constituent amylin within the hetero-dimer when compared with the amylin monomer alone. Our results provide new molecular insights into understanding the neurotoxicity of the hetero-oligomers associated with the cross-talk between amyloid diseases.

Keywords

• amyloid aggregates
• protein folding
• molecular dynamics
• lipid rafts
• protein misfolding disease
• Alzheimer’s