Molecular biology of transmissible spongiform encephalopathies

Weissmann, Charles

doi:10.1016/0014-5793(96)00610-2

Cited by 157 publications

(117 citation statements)

References 68 publications

(73 reference statements)

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“…In particular, the combination of the results presented in this paper with earlier findings that the polypeptide segment 90-120 is also protected against protease K digestion in PrP Sc [6,7] emphasizes that there is a major change in the structural arrangement of the residues 90-120 in PrP c and PrP Sc .…”

Section: Discussionsupporting

confidence: 75%

“…TSEs have been linked with a conformational polymorphism of the 'prion protein' (PrP) [5], where a disease-related transformation of the ubiquitous cellular form of the protein, PrP c , into the infectious scrapie form, PrP Sc , is believed to consist of a change from a predominantly a-helical protein to a P-sheet-containing fold [6,7]. Considering the central role thus attributed to PrP, investigations of the three-dimensional structure of this protein are of keen interest.…”

Section: Introductionmentioning

confidence: 99%

“…After separation from the cell membrane, it is a water-soluble, protease K-sensitive protein for which circular dichroism (CD) spectroscopy indicates a high content of helical secondary structure [12,13]. PrP Sc has so far only been observed as an insoluble oligomer that displays resistance to protease K digestion and has characteristics of an amyloid [6,7]. Based on Fourier transform reflection infrared spectroscopy it was concluded that a significant percentage of the polypeptide chain in p r pSc f orms (3-S heet secondary structure [12,13].…”

Section: Introductionmentioning

confidence: 99%

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NMR characterization of the full‐length recombinant murine prion protein, mPrP(23–231)

Riek¹,

Hornemann²,

Wider³

et al. 1997

FEBS Letters

688

486

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NMR characterization of the full‐length recombinant murine prion protein, mPrP(23–231)

Riek¹,

Hornemann²,

Wider³

et al. 1997

FEBS Letters

688

486

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“…The best known animal forms of the disease are scrapie and bovine spongiform encephalopathy; the human versions include kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia (1)(2)(3)(4). All of these disorders are characterized by cerebral accumulation of an abnormal protein, designated PrP res , which has a strong tendency to aggregate into insoluble fibrils.…”

mentioning

confidence: 99%

pH-dependent Stability and Conformation of the Recombinant Human Prion Protein PrP(90–231)

Świętnicki

Petersen

Gambetti

et al. 1997

Journal of Biological Chemistry

252

242

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A recombinant protein corresponding to the human prion protein domain encompassing residues 90 -231 (huPrP(90 -231)) was expressed in Escherichia coli in a soluble form and purified to homogeneity. Spectroscopic data indicate that the conformational properties and the folding pathway of huPrP(90 -231) are strongly pH-dependent. Acidic pH induces a dramatic increase in the exposure of hydrophobic patches on the surface of the protein. At pH between 7 and 5, the unfolding of hPrP(90 -231) in guanidine hydrochloride occurs as a two-state transition. This contrasts with the unfolding curves at lower pH values, which indicate a three-state transition, with the presence of a stable protein folding intermediate. While the secondary structure of the native huPrP(90 -231) is largely ␣-helical, the stable intermediate is rich in ␤-sheet structure. These findings have important implications for understanding the initial events on the pathway toward the conversion of the normal into the pathological forms of prion protein.Prion diseases comprise a group of transmissible neurodegenerative disorders. The best known animal forms of the disease are scrapie and bovine spongiform encephalopathy; the human versions include kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia (1-4). All of these disorders are characterized by cerebral accumulation of an abnormal protein, designated PrP res , which has a strong tendency to aggregate into insoluble fibrils. According to the "protein only hypothesis" (5, 6), PrP res constitutes the sole component of the infectious pathogen responsible for the transmission of prion disease.PrP res is derived from a host-encoded glycoprotein, the prion protein (PrP). 1 The transition between the cellular form of PrP, designated PrP C , and PrP res occurs by a post-translational mechanism and appears to take place without any detectable covalent modifications to the protein molecule (7). One of the main characteristics distinguishing PrP C from PrP res is the resistance of the latter to proteolytic digestion (8, 9). Furthermore, recent spectroscopic studies indicate that the two isoforms have profoundly different conformation: while the secondary structure of PrP C consists largely of ␣-helices (10), PrP res appears to be rich in ␤-sheet structure (10 -13). In line with these observations, the current view is that prion diseases may be classified as disorders resulting from abnormal protein folding and that the key event in the pathogenic process is the transition between the "benign" conformation of PrP C and the "pathological" conformation of PrP res . It is believed that the propagation of the disease can be described according to nucleation-dependent polymerization and/or template-assisted models (6, 14 -17). However, the molecular mechanism and potential intermediate forms of PrP underlying the conformational transition between the normal and pathogenic isoforms of the protein remain unknown.Recent studies have provided an insight into the three-dimens...

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“…These disorders can be sporadic, inherited, or acquired by infection [1–4]. Prion diseases include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in elk and deer, as well as Creutzfeldt-Jacob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Strässler-Scheinker syndrome (GSS) and kuru in humans.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic characterization for the denatured state of bovine prion protein and the BSE Associated variant E211K

Hwang

Nicholson

2018

Prion

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Propagation of transmissible spongiform encephalopathies involves the conversion of cellular prion protein, PrPC, into a misfolded oligomeric form, PrPSc. The most common hereditary prion disease is a genetic form of Creutzfeldt-Jakob disease in humans, in which a mutation in the prion gene results in a glutamic acid to lysine substitution at position 200 (E200K) in PrP. In cattle, the analogous amino acid substitution is found at residue 211 (E211K) and has been associated with a case of bovine spongiform encephalopathy. Here, we have compared the secondary structure of E211K to that of wild type using circular dichroism and completed a thermodynamic analysis of the folding of recombinant wild type and E211K variants of the bovine prion protein. The secondary structure of the E211K variant was essentially indistinguishable from that of wild type. The thermodynamic stability of E211K substitution showed a slight destabilization relative to the wild type consistent with results reported for recombinant human prion protein and its mutant E200K. In addition, the E211K variant exhibits a similarly compact denatured state to that of wild type based upon similar m-value and change in heat capacity of unfolding for the proteins. Together these results indicate that residual structure in the denatured state of bPrP is present in both the wild type protein and BSE associated variant E211K. Given this observation, as well as folding similarities reported for other disease associated variants of PrP it is worth consideration that functional aspects of PrP conformation may play a role in the misfolding process.

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Molecular biology of transmissible spongiform encephalopathies

Cited by 157 publications

References 68 publications

NMR characterization of the full‐length recombinant murine prion protein, mPrP(23–231)

NMR characterization of the full‐length recombinant murine prion protein, mPrP(23–231)

pH-dependent Stability and Conformation of the Recombinant Human Prion Protein PrP(90–231)

Thermodynamic characterization for the denatured state of bovine prion protein and the BSE Associated variant E211K

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