Mapping the interactions between prion protein (PrPC) and prion protein fibrils (PrPSc).

Abstract

Transmissible spongiform encephalopathies (TSEs), prion diseases, arise when normal prion protein (PrPC) misfolds and accumulates, forming prion fibrils (PrPSc) in the brain. Normal prion protein is GPI-anchored to the outer leaflet of the plasma membrane. Therefore, under pathological conditions, templated misfolding and aggregation occur on, or close to, the cell surface. However, this process of misfolding is distinct from neurotoxicity signaling pathways. Experimentally resolved three-dimensional structures of prion fibrils show at least two distinct populations: PIRIBS and 4-rungB. Although these structures provide valuable insight into fibril morphology, the mechanism responsible for templating prion protein misfolding largely remains unknown. In our project, we aim to characterize the modes of recognition between the prion proteins and fibrils on the surface of the cell membrane, using computational structural bioinformatics techniques. The results suggest that fibril-cell surface interactions are differentially driven by the electrostatics of the unique fibril morphologies. Our mapping of the binding interface of prion protein and fibril indicates a distribution of recognition sites, including the lateral surface and edge of the fibril. We will discuss our results considering the hypothesis that a distribution of protein-fibril recognition events leads to distinct outcomes, either scaffolding templated misfolding or triggering neurotoxic signaling. We will propose implications in terms of anti-prion druggable pathways as they relate to the potential mechanisms of neurotoxicity.