A phase separation hypothesis for the biological function of PrP: the role of multivalent interactions at the plasma membrane

Although the prion protein (PrP) is well established as the etiological agent of transmissible spongiform encephalopathies, its biological function remains under debate. Native, cellular PrP (PrPC) is a glycosylphosphatidylinositol-anchored protein that interacts with various proteins and other molecular ligands at the cell surface, triggering diverse cellular responses such as neuritogenesis and neuroprotection. PrPC has been proposed to act as a scaffolding protein, facilitating the assembly of multicomponent complexes at the membrane, with signal transduction occurring through the recruitment of transmembrane proteins. Recent findings demonstrate that PrP undergoes phase separation (PS) in vitro and in cellulo, mostly driven by its multivalency, intrinsically disordered N-terminal domain, and ability to bind polyanions. Considering recent data showing that membrane multicomponent complexes may assemble through PS, we discuss the possible formation of biomolecular condensates containing PrP at the membrane in light of previously described PrP protein ligands. In this mini-review, we examine PrP’s interactions with key ligands such as epidermal growth factor receptor, apolipoprotein E, amyloid β oligomers, α-synuclein, N-methyl-D-aspartate receptor, postsynaptic density protein 95, integrin β1, and tau, assessing their relevance in PS-mediated condensate formation. These proteins were selected based on their direct or indirect interaction with PrP, biological effects, presence in a membrane environment, and evidence of participation in biomolecular condensates. Based on current evidence, we propose that PS may be a fundamental mechanism underlying PrP’s biological role in the membrane.