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.

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 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.

Structure of PrP^CStructure of PrPC

1hjm, 1 NMR models ()

Related:

1e1g, 1e1j, 1e1p, 1e1s, 1e1u, 1e1w, 1hjn

Structural annotation:
Resources:	CATH : 1Hjma00 InterPro : Ipr000817 Pfam : PF00377 SCOP : d1hjma_ UniProt : P04156

Functional annotation:
Cellular component:	extrinsic to membrane plasma membrane Golgi apparatus membrane raft cytoplasm membrane endoplasmic reticulum
Biological process:	protein homooligomerization cellular copper ion homeostasis metabolic process response to oxidative stress
Molecular function:	copper ion binding protein binding GPI anchor binding tubulin binding microtubule binding

Evolutionary conservation:

Toggle Conservation Colors:	Rows = identical sequences:
Further Information:	Caveats, Explanation, Complete Results at ConSurfDB

Resources:

FirstGlance, OCA, RCSB, PDBsum

Coordinates:

save as pdb, mmCIF, xml

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 ^[1].

, and the structure of PrP^C 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 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.

Models of PrP^Sc structureModels of PrPSc structure

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^[3]. There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc, 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).

Prion strainsPrion strains

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.

Selected PrP structuresSelected PrP structures

All structures determined by NMR unless otherwise specified

Human PrPHuman PrP

1qlx HuPrP residues 23-230
1qm0 HuPrP residues 90-230
1qm2 HuPrP residues 121-230
1i4m HuPrP residues 119-226 (determined by X-ray crystallography)
1fkc HuPrP,E200K residues 90-231 (genetic prion disease)
1h0l HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog Doppel

Other species PrPsOther species PrPs

1xyx Mouse PrP residues
1b10 Syrian hamster PrP residues 90-231
1dwy Cow PrP residues 121-230
1uw3 Sheep PrP (determined by X-ray crystallography)
1xu0 Frog PrP residues 98-226
1u3m Chicken PrP
1u5l Turtle PrP residues 121-226

ReferencesReferences

↑ Zahn, R. et al. (2000) NMR solution structure of the human prion protein Proc. Natl. Acad. Sci. USA 97, 145-150
↑ [[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}}
↑ Template:Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog 'Proc. Natl. Acad. Sci. USA'' '''102''', 651-655

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Kurt Giles, Jaime Prilusky, Eran Hodis, Claudio Garutti, Michal Harel, Joel L. Sussman

[1] Zahn, R. et al. (2000) NMR solution structure of the human prion protein Proc. Natl. Acad. Sci. USA 97, 145-150

[2] [[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}}

[3] Template:Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog 'Proc. Natl. Acad. Sci. USA'' '''102''', 651-655

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Prion protein