Prion protein: Difference between revisions

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

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-The prion protein (PrP) is a cell surface glycoprotein. PrP can exist in two alternatively folded confirmations: the cellular isoform (PrP<sup>C</sup>) can undergo a structural conversion to a 'scrapie' or disease associated isoform termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.
+<StructureSection load='1hjm' size='350' side='right' scene='Prion_protein/Cartoon/4' caption=' NMR structure of human prion protein precursor globular domain (PDB code [[1hjm]])'>
-=Structure of PrP<sup>C</sup>=
-{{STRUCTURE_1hjm |  PDB=1hjm  |  SCENE=  }}
-PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, with a single disulfide bond. The presence of the N-terminus has little impact on the structure of the C-terminal domain <ref>1</ref>.
-The structure is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians.
+The [[prion protein]] (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>.
-ALthough having a similar overall fold, the X-ray structure of sheep PrP was dimeric
+==Prion diseases==
+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.
-=Models of PrP<sup>Sc</sup> structure=
+In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> 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 PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.
-Circular dichroism studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup>
-There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup>
+==Structure of PrP<sup>C</sup>==
-<ref>10</ref>
+PrP<sup>C</sup> has an [http://proteopedia.org/w/Intrinsically_Disordered_Protein intrinsically disordered] N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short <scene name='Prion_protein/Cartoon/3'>β-strands</scene>. A <scene name='Prion_protein/1hjm_disulfide_bond/4'>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.
-=Genetic prion diseases=
-A number of mutations in PrP have been identified which correlate with a high incidence of prion disease. The structure of HuPrP,E200K was determined nd shown to be To date, structural studies of all mutant PrP<sup>C</sup> have extremely similar structures to wild type PrP<sup>C</sup>, suggesting a kinetic basis for the difference in converting to PrP<sup>Sc</sup>.
-=Prion strains=
+==Models of PrP<sup>Sc</sup> structure==
-The strain phenomenon of prions ( ) was initially difficult to equate with the
+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]]).
+==Prion 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 PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.
-=Selected PrP structures=
+==Hot Spots in PrP<sup>C</sup> for pathogenic conversion==
-All structures determined by NMR unless otherwise specified
+There are several <scene name='Prion_protein/Prion_point_mutations/1'>point mutations associated with known human prion diseases</scene> (P102L, P105L, A117V, M129V, G131V, Y145Stop, R148H, Q160Stop, D178N, V180I, T183A, H187R, T188R, E196K, F198S, E200K, D202N, V203I, R208H, V210I, E211Q, Q212P, and Q217R).
-==Human PrP==
+The pathogenic conversion process from PrP<sup>C</sup> to PrP<sup>Sc</sup> could be related to the thermal stability of PrP<sup>C</sup> <ref>Kuwata, K. ''et al.'' (2007) Hot spots in prion protein for pathogenic conversion ''Proc. Natl. Acad. Sci. USA''  '''104''', 11921–11926</ref>, since the mutations related to familial forms of the prion diseases are rather concentrated in helices 2 and 3, and the thermodynamical stability profile shows that diverse residues in helices 2 and 3 are less stable <ref>Kuwata, K. ''et al.'' (2002) Locally disordered conformer of the hamster prion protein: a crucial intermediate to PrP<sup>Sc</sup> ''Biochemistry ''  '''41''', 12277–12283</ref>.
-* [[1qlx]] HuPrP residues 23-230
+Moreover, the conversion might also be related with the global conformational fluctuation of PrP<sup>C</sup>, as a Carr–Purcell–Meiboom–Gill relaxation–dispersion
-* [[1qm0]] HuPrP residues 90-230
+study revealed that slow fluctuation on a time scale of microseconds to milliseconds occurs, again, in helices 2 and 3<ref>Kuwata, K. ''et al.'' (2004) Slow conformational dynamics in the hamster prion protein ''Biochemistry''  '''43''', 4439-4446</ref>,<ref>Korzhnev, D.M. ''et al.'' (2004) Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR ''Nature''  '''430''', 586-590</ref>.
-* [[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 PrPs==
+== See Also ==
-* [[1xyx]] Mouse PrP residues
+* [[Prion]]
-* [[1b10]] Syrian hamster PrP residues 90-231
+* [[Journal:JBSD:4]]
-* [[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
-=References=
+==References==
- {{Reflist}}
-Zahn, R. ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA''  '''97''', 145-150
-Zahn R. et al. (2003) NMR structure of a variant human prion protein with two disulfide bridges'' J. Mol. Biol.'' '''326''', 225-34.
 <references/>
+</StructureSection>
+[[Category:Topic Page]]