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 | The naturally ocuring prion diseases include [http://en.wikipedia.org/wiki/Creutzfeldt-Jakob_disease Creutzfeldt-Jakob disease] (CJD) in people, [http://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy bovine spongiform encephalopathy] (BSE) commonly known as "mad cow" disease, [http://en.wikipedia.org/wiki/Scrapie scrapie] in sheep and goats, and [http://en.wikipedia.org/wiki/Chronic_wasting_disease chronic wasting disease] in deer. 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. | ||
Revision as of 09:58, 21 December 2008
The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrPC) and a disease associated isoform termed PrPSc.
Prion diseasesPrion 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 deer. In all cases post mortem analysis of brain tissue is characterized by aggregates of PrPSc. The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrPC is converted into PrPSc that in turn initiates an autocatalytic refolding cascade of PrPC in a template-dependent manner.
In sporadic prion disease, the spontaneous refolding or misfolding of PrPC into PrPSc initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the wild type protein. Infectious etiology is explained by introduction of exogenous PrPSc which then initiates refolding of endogenous PrPC.
Structure of PrPCStructure of PrPC
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| 1hjm, 1 NMR models () | |||||||||
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| Related: | 1e1g, 1e1j, 1e1p, 1e1s, 1e1u, 1e1w, 1hjn | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
PrPC 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 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 [1]. The structure of PrPC is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians[2]. 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 PrPSc structureModels of PrPSc structure
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrPSc had very different proportions of α-helices and β-sheet to PrPC[3]. There are a number of technical obstacles in determining the atomic resolution structure of PrPSc, and the most detailed information to date has been obtained by electron microscopy of 2D crystals[4]. 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[5]. Support for this β-helical model comes from the structure of the fungal prion Het-s (2rnm).
Prion strainsPrion strains
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) 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 PrPSc. One potential mechanism for this is alternate threading of the β-helix.
Selected PrP structuresSelected PrP structures
All structures determined by NMR spectroscopy unless otherwise specified
Human PrPHuman PrP
- 1qlx Residues 23-230
- 1qm0 Residues 90-230
- 1qm2 Residues 121-230
- 1i4m Determined by X-ray crystallography
- 1fkc E200K mutant (genetic prion disease)
PrP from other speciesPrP from other species
- 1xyx Mouse PrP
- 1b10 Syrian hamster PrP
- 1dwy Cow PrP
- 1uw3 Sheep PrP (determined by X-ray crystallography)
- 1xu0 Frog PrP
- 1u3m Chicken PrP
- 1u5l Turtle PrP
ReferencesReferences
- ↑ Zahn, R et al. (2000) NMR solution structure of the human prion protein Proc. Natl. Acad. Sci. USA 97, 145-150
- ↑ Calzolai, L et al. (2005) Prion protein NMR structures of chicken, turtle, and frog Proc. Natl. Acad. Sci. USA 102, 651-655
- ↑ 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
- ↑ Wille H et al. (2002) Structural studies of the scrapie prion protein by electron crystallography Proc. Natl. Acad. Sci. USA 99, 3563-3568
- ↑ 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