Molecular Determinants Of The Interaction Between The C-Terminal Domain Of Alzheimer'S Beta-Amyloid Peptide And Apolipoprotein E Alpha-Helices

In a previous work, we predicted and demonstrated that the 29-42-residue fragment
of beta-amyloid peptide (Abeta peptide) has in vitro capacities close to those of
the tilted fragment of viral fusion proteins. We further demonstrated that
apolipoprotein E2 and E3 but not apolipoprotein E4 can decrease the fusogenic
activity of Abeta(29-42) via a direct interaction. Therefore, we suggested that
this fragment is implicated in the neurotoxicity of Abeta and in the protective
effects of apolipoprotein E in Alzheimer's disease. Because structurally related
apolipoproteins do not interact with the Abeta C-terminal domain but inhibit
viral fusion, we suggested that interactions existing between fusogenic peptides
and apolipoproteins are selective and responsible for the inhibition of fusion.
In this study, we simulated interactions of all amphipathic helices of
apolipoproteins E and A-I with Abeta and simian immunodeficiency virus (SIV)
fusogenic fragments by molecular modeling. We further calculated
cross-interactions that do not inhibit fusion in vitro. The results suggest that
interactions of hydrophobic residues are the major event to inhibit the fusogenic
capacities of Abeta(29-42) and SIV peptides. Selectivity of those interactions is
due to the steric complementarity between bulky hydrophobic residues in the
fusogenic fragments and hydrophobic residues in the apolipoprotein C-terminal
amphipathic helices.