Prion protein: Difference between revisions
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<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]])'> | |||
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>. | 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>. | ||
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==Structure of PrP<sup>C</sup>== | ==Structure of PrP<sup>C</sup>== | ||
PrP<sup>C</sup> has | 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. | 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 PrP<sup>Sc</sup> structure== | ==Models of PrP<sup>Sc</sup> structure== | ||
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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. | 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. | ||
== | ==Hot Spots in PrP<sup>C</sup> for pathogenic conversion== | ||
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). | |||
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>. | |||
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 | |||
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>. | |||
=== | == See Also == | ||
* [[Prion]] | |||
* [[Journal:JBSD:4]] | |||
* [[ | |||
* [[ | |||
==References== | ==References== | ||
<references/> | <references/> | ||
</StructureSection> | |||
[[Category:Topic Page]] | |||
Latest revision as of 06:32, 28 February 2019
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 diseasesThe 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 PrPCPrPC has an intrinsically disordered N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short . 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 structureFourier 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 strainsThe 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. Hot Spots in PrPC for pathogenic conversionThere are several (P102L, P105L, A117V, M129V, G131V, Y145Stop, R148H, Q160Stop, D178N, V180I, T183A, H187R, T188R, E196K, F198S, E200K, D202N, V203I, R208H, V210I, E211Q, Q212P, and Q217R). The pathogenic conversion process from PrPC to PrPSc could be related to the thermal stability of PrPC [6], 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 [7]. Moreover, the conversion might also be related with the global conformational fluctuation of PrPC, as a Carr–Purcell–Meiboom–Gill relaxation–dispersion study revealed that slow fluctuation on a time scale of microseconds to milliseconds occurs, again, in helices 2 and 3[8],[9]. See AlsoReferences
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