Loss of the Central Region Reshapes the Dynamic Landscape of the Cellular Prion Protein and Its Plasma Membrane Interaction

Prion diseases are fatal neurodegenerative disorders driven by the conversion of the cellular prion protein (PrP) into a misfolded, pathogenic conformer. Beyond serving as a substrate for prion propagation, PrP is also thought to mediate neurotoxic signaling. Within this framework, the central region of PrP has emerged as a critical regulatory element. Notably, deletion of residues 105-125 ({Delta}CR) leads to spontaneous neurodegeneration in vivo and induces abnormal ionic currents in cultured cells and primary neurons, indicating that this region is essential for controlling the toxicity of the N-terminal domain. Current models propose that the N-terminus functions as a toxic effector whose activity is modulated by the C-terminal domain. This intramolecular interplay is likely central to the physiological role of PrP, and its disruption may contribute to neurodegeneration. Here, we investigated how deletion of the central region affects the structure and dynamics of full-length PrP. We generated membrane-bound models of full-length, diglycosylated wild-type (WT) PrP and the neurotoxic {Delta}CR mutant, and compared their conformational dynamics using molecular dynamics simulations. The two proteins exhibited markedly distinct behaviours. WT PrP adopted a more compact conformational ensemble of the N-terminal domain, consistent with stabilizing interactions between the flexible N-terminus and the globular C-terminal domain. In contrast, the {Delta}CR variant displayed more extended conformations and a substantial redistribution of intramolecular contacts, including the loss of specific interactions between the disordered N-terminal tail and the globular domain. This altered structural organization was accompanied by an increased propensity of the N-terminal domain to approach the membrane surface in the mutant. Our results provide a molecular model in which the central region engages intramolecular interaction networks that ultimately help regulate N-terminal residence at the plasma membrane, offering mechanistic insight into how CR deletion shifts the conformational ensemble toward membrane-associated states that may be associated with neurotoxic activity.