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Mouse Prion Protein Domain PrP(121-231)

Mouse Prion Protein Domain PrP(121-231). Andreas Razen Geometric Computations in Molecular Biology 2 May 2007. Prion Protein. Located in cell surface (brain, nervous system) Protects cell against oxidative stress (free radicals lacking electrons)

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Mouse Prion Protein Domain PrP(121-231)

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  1. Mouse Prion ProteinDomain PrP(121-231) Andreas Razen Geometric Computations in Molecular Biology 2 May 2007

  2. 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

  3. 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

  4. Structure of Mouse PrP(121-231) • 3 right-handed α-helices and 1 two-stranded anti-parallel β-sheet • Most point mutation sites are located in second and third helix (all are identical with human PrP)

  5. 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

  6. Ramachandran Plot

  7. 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)

  8. Same primary structure –different secondary structure • Presence of β-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

  9. Conformation change

  10. Protein Aggregation Diseases

  11. Thank you!

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