Prion protein
From Proteopedia
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 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 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 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 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 [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 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 PrP(sup)Sc</sup>, 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]
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Kurt Giles, Joel L. Sussman, Jaime Prilusky, Michal Harel, Claudio Garutti, Eran Hodis
