Lipids enhance apolipoprotein C-II-derived amyloidogenic peptide oligomerization but inhibit fibril formation

Andrew Hung, Michael D W Griffin, Geoffrey J Howlett, Irene Yarovsky
Journal of Physical Chemistry. B 2009 July 16, 113 (28): 9447-53
We investigated the effect of submicellar lipids on amyloid fibril formation. Thioflavin T fluorescence studies showed that submicellar levels of the short-chain phospholipids, dipentanoylphosphatidylcholine and dihexanoylphosphatidylcholine, strongly inhibited amyloid fibril formation by an 11-residue peptide derived from human apolipoprotein C-II (apoC-II(60-70)). In contrast, sedimentation equilibrium analysis of these peptide-lipid mixtures indicated the presence of soluble oligomeric complexes. To acquire insight into the atomic level influences of these lipids on the initial stages of aggregation of the peptide, we performed molecular dynamics (MD) simulations coupled with umbrella sampling to determine dimerization free energies of a number of beta-stranded and random coil dimer complexes, both in the presence and absence of lipids. The simulations indicate that, in contrast to their inhibitory effects on fibril formation, short-chain phospholipids promote the formation and stabilization of dimers by enhancing intersubunit hydrophobic interactions. On the basis of these experimental and computational results, we propose that peptide-bound lipids can inhibit amyloid fibril formation by trapping of dimers and other oligomeric species in diverse nonfibril forming conformations, reducing their likelihood of acquiring subunit conformations prone to fibril nucleation and growth. In light of the demonstrated cytotoxicity of amyloid peptide oligomers, our results suggest that, by enhancing the stability of oligomeric peptide species, the presence of solvated lipids may contribute to the cytotoxicity of fibrillogenic proteins and peptides.

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