What is the difference between prpc and prpsc

Dimers in solution show the intact intramolecular disulphide bridge. Consequently, dimerization is not induced by oxidizing the disulphide bridge and reforming it in an intermolecular structure. The latter situation was, however, found in a recent crystal structure of a dimer of PrP — 31 ; dimers were formed by domain swapping and intermolecular disulphide bridging. Whether this structure is a consequence of the long-time crystallization, or might indicate a physiological state, cannot be stated at present.

These models assume that helix 2 and helix 3 are unchanged in accordance with antibody binding data, but they are incomplete in the sense that they are models for isolated molecules whereas PrP Sc as well as PrP 27—30 were found only in aggregated forms. Thus, one has to assume that the PrP Sc structure is stabilized by intermolecular interactions. A new approach was followed by Wille from Prusiner's laboratory who was able to prepare two-dimensional crystalline-like arrays of PrP Sc - or PrP Sc -like molecules Those samples were studied by electron microscopy and, because of the crystalline-like arrangement, images could be reconstructed from the repetitive unit with fairly high resolution.

A hexagonal symmetry was visible, but it could not be decided whether one unit is built from 3 or 6 molecules. The model is depicted in Plate 1V. Most probably, the model shown in Plate IV is not the final description of the structure of PrP Sc , but it is the best model currently available and takes into account both electron microscopic and spectroscopic data as well as the intermolecular stabilization of the PrP Sc structure.

Structure of PrP Sc -like oligomers. Reconstruction of the oligomeric structure from electron microscopic analysis of two-dimensional crystals. Structural and other chemical and physical properties of PrP C and PrP Sc in the purified state have been described above. Since no functional test for PrP C is available, it is more accurate to speak about a PrP C -like conformation when the such properties are found.

The denaturation of the globular domain of recombinant PrP — by addition of up to 8 M urea was analyzed quantitatively by recording the ellipticity at nm One co-operative transition was obtained at pH 7. At pH 4. From the reversibility of the denaturation process, it was concluded that the PrP C -like conformation is the state of lowest free energy in buffer without detergent.

This conclusion might be restricted, however, to the fragment PrP — Similar experiments, but also taking into account the mechanism of re-folding by kinetic analysis, were carried out on recombinant PrP 89— from mouse which is the recombinant equivalent of PrP 27—30 Then the transition to the PrP Sc -like conformation was induced by slightly denaturing conditions, e. Also, these experiments were carried out at acidic pH 4. It is not known whether this finding is relevant to PrP C to PrP Sc conversion in nature because the intramolecular disulphide bridge is present in both states and in all other conversion experiments the disulphide bridge was not opened transiently The earliest studies on the in vitro conversion were carried out with natural PrP and at neutral pH Although natural PrP was used which was infectious before the conversion, infectivity could not be re-established.

These experiments were closest to natural conditions if the low concentrations of SDS were regarded as a membrane-like environment. Applying the same conversion system to recombinant PrP 90— , systematic studies of the influence of varying SDS concentrations were carried out and several intermediate states described Fig.

As recently determined Nagel-Steger et al , unpublished , the oligomeric state with 12—16 molecules is of particular interest for further biophysical studies since it is stable in solution. In buffer without detergent at pH 7, the PrP C -like as well as the PrP Sc -like conformations can be established, but the stable state is the PrP Sc -like conformation, and the conversion can be induced by different detergents, even in very low concentrations see also Xiong et al Intermediates in the in vitro conversion of recombinant PrP 90— What is the conclusion from all the in vitro conversion studies?

Evidently, the thermodynamically stable state is the PrP Sc -like state, and this would be true for lysosomal acidic pH or the cell-surface neutral pH. A high activation barrier renders the transition very slow i.

If the PrP C -conformation is not the thermodynamically stable state, but only metastable, the question remains why a transition to PrP Sc does not occur much more frequently in nature as a spontaneous transition. It is, however, not a discrepancy if one takes into account that PrP C is anchored in the lipid membrane, and all studies described were carried out in aqueous buffer. Consequently, as an additional transition of PrP C , one has to include the distribution between the aqueous and the lipid phase which would definitely stabilize PrP C in nature to prevent a spontaneous transition.

Correspondence to: Prof. The exceptionally small size of the scrapie agent. Biochem Biophys Res Commun ; 22 : — Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science ; : — A cellular gene encodes scrapie PrP 27—30 protein. Cell ; 40 : — Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell ; 46 : — Griffith JS. Self-replication and scrapie. Nature ; : —4. Scrapie and cellular prion proteins share polypeptide epitopes. J Infect Dis ; : — Scrapie prions.

Annu Rev Microbiol ; 43 : — Weissmann C. Molecular biology of prion diseases. Trends Cell Biol ; 4 : 10 —4. Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol ; 11 : —8. Scrapie prion rod formation in vitro requires both detergent extraction and limited proteolysis. J Virol ; 65 : — High-level expression and characterization of a purified residue polypeptide of the prion protein. Biochemistry ; 35 : — Prion protein expression in Chinese hamster ovary cells using a glutamine synthetase selection and amplification system.

Protein Eng ; 10 : — Scrapie prions aggregate to form amyloid-like birefringent rods. Cell ; 35 : — Abnormal fibrils from scrapie-infected brain. Acta Neuropathol ; 54 : 63 — Eight prion strains have PrP Sc molecules with different conformations. Nat Med ; 4 : — Nature ; : — Search for a putative scrapie genome in purified prion fractions reveals a paucity of nucleic acids. J Gen Virol ; 72 : 37 — Further analysis of nucleic acids in purified scrapie prion preparations by improved return refocusing gel electrophoresis RRGE.

J Gen Virol ; 73 : —9. Prion rods contain small amounts of two host sphingolipids as revealed by thin-layer chromatography and mass spectrometry. Biol Chem ; : — Molecular characteristic of prion rods purified from scrapie-infected hamster brain. Prion rods contain an inert polysaccharide scaffold.

Secondary structure analysis of the scrapie-associated protein PrP 27—30 in water by infrared spectroscopy. Biochemistry ; 30 : — Conformational transitions, dissociation, and unfolding of scrapie amyloid prion protein. J Biol Chem ; : — NMR structure of the mouse prion protein domain PrP — Nature ; : —2. Solution structure of a residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform.

Mass spectrometry of peptides derived from PrPSc has revealed numerous modifications including two N-linked carbohydrate moieties, removal of an amino-terminal signal sequence, and alternative COOH termini. Other experiments suggest that the N-linked oligosaccharides are not necessary for PrPSc formation. Although detailed comparison of PrPSc with PrPC is required, there is no obvious way in which any of the modifications might confer upon PrPSc its unusual physical properties and allow it to act as a component of the prion.

If no chemical difference is found between PrPC and PrPSc, then the two isoforms of the prion protein may differ only in their conformations or by the presence of bound cellular components. Prion , 8 1 , The structure of the infectious prion protein. Pressure—temperature folding landscape in proteins involved in neurodegenerative diseases and cancer. Biophysical Chemistry , , Prion , 7 6 , Journal of Molecular Biology , 18 , Serpa , Aileen P. Wishart , Evgeniy V.

Petrotchenko , Christoph H. Using multiple structural proteomics approaches for the characterization of prion proteins. Journal of Proteomics , 81 , Journal of Biological Chemistry , 1 , Allosteric post-translational modification codes. Trends in Biochemical Sciences , 37 10 , Petrotchenko , Jason J. Serpa , Darryl B. Hardie , Mark Berjanskii , Bow P. Suriyamongkol , David S. Wishart , Christoph H. Journal of Biological Chemistry , 23 , Using small molecule reagents to selectively modify epitopes based on their conformation.

Prion , 6 2 , Franco , Tapas K. Identification and characterization of a bactericidal and proapoptotic peptide from cycas revoluta seeds with DNA binding properties. Journal of Cellular Biochemistry , 1 , FEBS Journal , 2 , Pair your accounts. Your Mendeley pairing has expired. Please reconnect. This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies.

Read the ACS privacy policy. Recently Viewed.