How prion fibrils marry conserved architecture with structural diversity and why it matters

Introduction
Prions are transmissible and invariably fatal amyloid fibrils formed from misfolded host-encoded prion protein (PrP). While the native cellular form (PrP^C) shares a conserved fold across species, the pathogenic form (PrP^Sc) exhibits conformational polymorphism both within and between species, giving rise to distinct prion strains and transmission barriers.

Objectives
To identify structural determinants underlying prion strain diversity and interspecies transmission barriers through atomic-resolution comparisons of prion fibrils from multiple host species.

Methods
Analysis of cryo-EM structures of rodent-adapted prion fibrils from terminally infected hamster and mouse brains, and a natural chronic wasting disease (CWD) prion fibril from deer.

Results and Discussion
All prion fibrils display a bi-lobed core architecture centred around a conserved disulfide (S-S) bridge. Structural alignment revealed three modular segments: the N-lobe, the disulphide-stapled (DS) hairpin, and the C-tail. The S-S bridge acts as a conformational anchor, allowing semi-independent folding of the N-lobe and DS hairpin, modulated by C-tail interactions. The N-lobes are multi-layered and heavily interlocked, appearing more conserved within species, while the C-lobes are structurally diverse and may distinguish strains. No single structural motif is universally shared across species. Variability in C-lobe conformation may explain the existence of prion quasispecies and contribute to crossing interspecies transmission barriers.

Conclusion
Prion strain diversity and transmission potential arise from the modular, conformational plasticity of PrP. Mapping PrP sequence variants onto known prion structures may support the prediction of strain behavior and zoonotic risk.