Conformational Reorganisation of Apolipoprotein E Triggered by Phospholipid Assembly

Abstract

Apolipoprotein E ( ApoE), a major determinant protein for lipid-metabolism, actively participates in lipid transport in central nervous system via high-affinity interaction with lipoprotein receptor LDLR. Prior evidences indicate that the phospholipids first need to assemble around apoE, before the protein can recognise its receptor. However, despite multiple attempts via spectroscopic and biochemical investigations, it is unclear what are the impact of lipid assembly on globular structure of apoE. Here, using a combination of all-atom and coarse-grained molecular dynamics simulations, we demonstrate that, an otherwise compact tertiary fold of monomeric apoE3 spontaneously unwraps in an aqueous phospholipid solution in two distinct stages. Interestingly, these structural reorganizations are triggered by an initial localised binding of lipid molecules to the C-terminal domain of the protein, which induce a rapid separation of C-terminal domain of apoE3 from the rest of its tertiary fold. This is followed by a slow lipid-induced inter-helix separation event within the N-terminal domain of the protein, as seen in an extensively long coarse-grained simulation. Remarkably, the resultant complex takes the shape of an `open conformation' of lipid-stabilised unwrapped protein, which intriguingly coincides with an earlier proposal by small-angle X-ray scattering (SAXS) experiment. The lipid-binding activity and the lipid-induced protein conformation are found to be robust across a monomeric mutant and wild-type sequence of apoE3. The `open' complex derived in coarse-grained simulation retains its structural morphology after reverse-mapping to all-atom representation. Collectively, the investigation puts forward a plausible structure of currently elusive conformationally activated state of apoE3, which is primed for recognition by lipoprotein receptor and can be exploited for eventual lipid transport.