The most infectious prion protein particles

Silveira, Jay R.; Raymond, Gregory J.; Hughson, Andrew G.; Race, Richard E.; Sim, Valerie L.; Hayes, Stanley F.; Caughey, Byron

doi:10.1038/nature03989

Cited by 843 publications

(852 citation statements)

References 25 publications

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“…Conversion efficacy is monitored by apparition of labeled, protease-resistant PrP Sc after 1-3 days incubation at 37˚C [50,111]. In a recent work, such a converting activity was reported to be dependent upon the size of PrP Sc aggregates used as seeds [182]. These studies supported the view that PrP Sc formation occurs through a nucleated polymerization process rather than a heterodimer mechanism.…”

Section: Cell-free Systemsmentioning

confidence: 64%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Section: Cell-free Systemsmentioning

confidence: 64%

Prion agent diversity and species barrier

2008

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“…2 It is yet to be established what structural relationship small toxic replicating oligomeric species have with the more mature amyloid fibers. 3 It is clear the structure, flexibility, and stability of native PrP C as well as folding intermediates of PrP are of significant interest to those studying the mechanism of prion misfolding and replication.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of a truncated prion protein, PrP(113–231), from ¹⁵N NMR relaxation: Order parameters calculated and slow conformational fluctuations localized to a distinct region

et al. 2009

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Prion diseases are associated with the misfolding of the prion protein (PrP C ) from a largely a-helical isoform to a b-sheet rich oligomer (PrP Sc ). Flexibility of the polypeptide could contribute to the ability of PrP C to undergo the conformational rearrangement during PrP C -PrP Sc interactions, which then leads to the misfolded isoform. We have therefore examined the molecular motions of mouse PrP C , residues 113-231, in solution, using 15 N NMR relaxation measurements. A truncated fragment has been used to eliminate the effect of the 90-residue unstructured tail of PrP C so the dynamics of the structured domain can be studied in isolation. 15 N longitudinal (T 1 ) and transverse relaxation (T 2 ) times as well as the proton-nitrogen nuclear Overhauser effects have been used to calculate the spectral density at three frequencies, 0, x N, and 0.87x H . Spectral densities at each residue indicate various time-scale motions of the main-chain. Even within the structured domain of PrP C , a diverse range of motions are observed. We find that removal of the tail increases T 2 relaxation times significantly indicating that the tail is responsible for shortening of T 2 times in full-length PrP C . The truncated fragment of PrP has facilitated the determination of meaningful order parameters (S 2 ) from the relaxation data and shows for the first time that all three helices in PrP C have similar rigidity. Slow conformational fluctuations of mouse PrP C are localized to a distinct region that involves residues 171 and 172. Interestingly, residues 170-175 have been identified as a segment within PrP that will form a steric zipper, believed to be the fundamental amyloid unit. The flexibility within these residues could facilitate the PrP C -PrP Sc recognition process during fibril elongation.

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“…Silveira et al attempted to determine the relationship between infectivity and converting activity with the size of various misfolded PrP-containing aggregates. Their analyses suggest that non-fibrillar particles, with masses equivalent to 14-28 PrP molecules, are the most efficient initiators of TSE disease [113]. Recently, amyloid fibrils prepared in vitro from full-length mouse recombinant prion protein (recPrP) were found to be as toxic to cells as soluble oligomeric intermediates [83].…”

Section: Introductionmentioning

confidence: 99%

Misfolding of the prion protein: linking biophysical and biological approaches

2008

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-Prion diseases are a group of neurodegenerative diseases that can arise spontaneously, be inherited, or acquired by infection in mammals. The propensity of the prion protein to adopt different structures is a clue to its pathological and perhaps biological role too. While the normal monomeric PrP is well characterized, the misfolded conformations responsible for neurodegeneration remain elusive despite progress in this field. Both structural dynamics and physico-chemical approaches are thus fundamental for a better knowledge of the molecular basis of this pathology. Indeed, multiple misfolding pathways combined with extensive posttranslational modifications of PrP and probable interaction(s) with cofactors call for a combination of approaches. In this review, we outline the current physico-chemical knowledge explaining the conformational diversities of PrP in relation with postulated or putative cellular partners such as proteic or non-proteic ligands.

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The most infectious prion protein particles

Cited by 843 publications

References 25 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Dynamics of a truncated prion protein, PrP(113–231), from ¹⁵N NMR relaxation: Order parameters calculated and slow conformational fluctuations localized to a distinct region

Misfolding of the prion protein: linking biophysical and biological approaches

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The most infectious prion protein particles

Cited by 843 publications

References 25 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Dynamics of a truncated prion protein, PrP(113–231), from 15N NMR relaxation: Order parameters calculated and slow conformational fluctuations localized to a distinct region

Misfolding of the prion protein: linking biophysical and biological approaches

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Dynamics of a truncated prion protein, PrP(113–231), from ¹⁵N NMR relaxation: Order parameters calculated and slow conformational fluctuations localized to a distinct region