Mouse Prion Protein Domain PrP121231

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Mouse Prion ProteinDomain PrP(121-231)

• Andreas Razen
• Geometric Computations in Molecular Biology
• 2 May 2007

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Prion Protein

• Located in cell surface (brain, nervous system)
• Protects cell against oxidative stress (free
  radicals lacking electrons)
• PrPC Prion Protein Cellular (normal form)
• PrPSc Scrapie form (infectious form)
• Change of conformation (chain reaction)
• sporadic
• genetic
• infection

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Protein Only Hypothesis

• A modified form of normal prion protein triggers
  infectious neurodegenerative diseases
• Prion Diseases
• affect brain and nervous system of humans and
  mammals not treatable fatal
• Creutzfeldt-Jakob disease (CJD) (Human)
• Bovine spongiform encephalopathy (BSE) (Cattle)
• Scrapie (Sheep)
• Feline spongiform encephalopathy (FSE) (Cats)
• PrPSc resistant to conventional sterilization
  methods (heat, radiation) in contrast to PrPC

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Structure of Mouse PrP(121-231)

• 3 right-handed a-helices and 1 two-stranded
  anti-parallel ß-sheet
• Most point mutation
• sites are located in
• second and third
• helix (all are identical
• with human PrP)

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Structure Elucidation PrP(121-231)

• Riek, Hornemann, Wider, Billeter, Glockshuber
  Wüthrich (1996)
• NMR
• Nuclei with magnetic spin align in very powerful
  external (static) magnetic field
• Alignment is perturbed by an additional
  electromagnetic field
• Magnetic nuclei absorb its energy (resonance)
• Depending on local chemical environment nuclei
  resonate at slightly different frequencies
• Structural information

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Ramachandran Plot
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Locations of selected residues

• Red Mutation related to prion deseases
• Blue Residues involved in species barrier
• Green solvent-accessible glycosilation sites
  (enhances solubility of protein)

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Same primary structure different secondary
structure

• Presence of ß-sheet in PrPC in contrast with
  model predictions (important for transition?)
• PrP occurs in two
• conformations not much
• differing in energy
• Dimer of PrPCPrPSc might
• form, destabilizing PrPC,
• causing conformational
• shift

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Conformation change
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Protein Aggregation Diseases
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Thank you!