Prion protein: Difference between revisions

The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP^C) and a disease associated isoform termed PrP^Sc.  

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. ''Post mortem'' analysis of brain tissue is characterterized by aggregates of PrP^Sc.

The spontaneous, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP^C is converted into PrP^Sc that initiates a cascade of autocatalytic refolding of PrP^C in a template-dependent manner.

In sporadic disease, the spontaneous refolding or misfolding of PrP^C into PrP^Sc initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to happen than in the wild type protein, Infectious etiology is explained by introduction of exogenous PrP^Sc which then initiates refolding of endogenous PrP^C.

PrP^C 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 single disulfide bond 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>.

, and the structure of PrP^C is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<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>.

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 structure is similar to other PrPs determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped with respect to the monomer and the disulphide bond is rearranged to be intermolecular between the dimer subunits.

Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP^Sc had very different proportions of α-helices and β-sheet to PrP^C<ref>{{Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog 'Proc. Natl. Acad. Sci. USA'' '''102''', 651-655}}</ref>.

There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup>, and the highest resolution structural information to date has been obtained by electron microscopy of 2D crystals. Differential binding of metal ions to these 2D crystals, and redacted constructs of PrP, provide a basis for structural modeling.

A model the N-terminal region and much of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure

Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).

The strain phenomenon of prion strains (disease subtype replicating with high fidelity and producing specific clinical, biochemical and neuropathological features) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP^Sc. One potential mechanism for this is alternate threading of the β-helix.