From PrPC to PrPSc: the change into a prion interactive model

A schematic, five-stage visual model of how the normal cellular prion protein is templated into the infectious, β-sheet-rich prion — then amplifies and causes disease. Based on data compiled in research_prion (see README and notes). Not to scale.

schematic — not to scale S–S nascent PrPᶜ pool N-terminal flexible tail (aa 23–120) octarepeat region (OR) N-glycans (N181, N197) structured C-terminal core (aa 121–231) · 3 α-helices · 2 β-strands inside disulfide (S–S) C179–C214 GPI anchor neuronal plasma membrane (lipid bilayer · GPI-anchored proteins) What changes when PrPᶜ becomes a prion? same amino-acid sequence — only the fold is rewritten, and a PrPˢᶜ “seed” (a β-sheet) does the rewriting 1 2 3 seed binds chain refolds unit joins PrPᶜ — native α-helical · soluble · protease-sensitive PrPˢᶜ — converted β-sheet-rich · insoluble · protease-resistant PrPˢᶜ seed — the template the fold is rewritten α-helix (coil) → β-strand the seed straightens & re-stacks the chain 1 · a PrPˢᶜ seed docks under the PrPᶜ molecule 2 · the seed is a β-sheet template — it forces the helices to unwind and re-form as β-strands 3 · refolded! the monomer is now PrPˢᶜ and stacks onto the seed — both are β-sheet stays the same: amino-acid sequence · covalent bonds changes: the fold — α-helices become β-strands that stack into an amyloid sheet a seed can appear sporadically, from a PRNP mutation, or by exposure to exogenous prions PrPˢᶜ fibril (template) growing end → PrPᶜ new PrPˢᶜ unit 1 2 3 dock template refold 4 grow free PrPᶜ pool 1 · PrPᶜ approaches the fibril's growing end 2 · the end is a β-sheet template — the docked protein is refolded into a β-unit 3 · new PrPˢᶜ unit added — the fibril is longer and ready for the next PrPᶜ one PrPˢᶜ fibril — growing at both ends fragmentation (breakage) new growing ends now 2 fibrils · 4 growing ends — seeds double at every break: 2 → 4 → 8 … autocatalytic amplification clinical threshold time (years — incubation) # prions (log) growth rate ∝ √[PrPᶜ] · incubation ∝ 1/growth rate prions spread cell-to-cell along neural pathways brain tissue — terminal disease vacuoles (“spongiform change”) astrocytosis PrP-amyloid plaque why it is always fatal prions self-propagate faster than cells can clear them no immune response is mounted (self-protein, no inflammation) neurons are post-mitotic — lost neurons are never replaced prions resist heat, proteases & standard sterilization clinical course years of silent incubation (kuru can exceed 50 yr) … … then rapid dementia, myoclonus, ataxia; death typically within months (~6 mo for sCJD). no cure · no vaccine · only supportive care
Stage 1 / 5