Protein-lipid interactions and anchoring modulate binding between Prion and Doppel protein globular domains and lipid membranes

The Prion protein is the molecular hallmark of the incurable prion diseases affecting mammals, including humans. The protein-only hypothesis states that the Prion protein plays a critical role in prion diseases by misfolding and accumulating into toxic aggregates. The cellular Prion protein (PrP^C) anchors to cholesterol- and sphingomyelin-rich plasma membrane domains. Prion protein conversion happens on the cell surface and is sensitive to membrane composition. A picture of the underlying driving forces that explain the effect of protein - lipid interactions in physiological conditions is needed to develop a structural model of Prion protein conformational conversion. To this end, we characterize the driving forces behind Prion protein-lipid interactions under physiological conditions. Molecular dynamics simulations mimic the dynamics of anchored PrP^C on model lipid patches. We also simulate the related Doppel protein on the same patches. Our simulations show that specific protein-lipid interactions and anchoring constraints favor particular binding sites on PrP^C and, to a lesser extent, Doppel. Intriguingly, the binding sites of PrP^C correspond to loops critical for aggregation and prion transmission. The membrane locally remodels to accommodate inserted protein residues. This work elucidates how interactions modulate the association of Prion and Doppel proteins with membranes to set the stage for understanding Prion protein conformational conversion.