Prion protein: Difference between revisions
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==Prion diseases== | ==Prion diseases== | ||
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>. | The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in [http://www.wikipedia.org/wiki/Cervidae cervids]. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>. | ||
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner. | The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner. | ||
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==Structure of PrP<sup>C</sup>== | ==Structure of PrP<sup>C</sup>== | ||
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }} | {{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }} | ||
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from | PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A <scene name='Prion_protein/1hjm_disulfide_bond/2'>single disulfide bond</scene> connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>. | ||
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits. | The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits. | ||
==Models of PrP<sup>Sc</sup> structure== | ==Models of PrP<sup>Sc</sup> structure== | ||
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP | Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP<sup>Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling. | ||
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]). | A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]). | ||