Identification of prion amyloid filaments in scrapie-infected brain

DeArmond, Stephen J.; McKinley, Michael P.; Barry, Ronald A.; Braunfeld, Michael B.; McColloch, John R.; Prusinert, Stanley B.

doi:10.1016/0092-8674(85)90076-5

Cited by 284 publications

(101 citation statements)

References 45 publications

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“…Infectious fibrils, known as prion rods, are composed of PrP 27-30, a fragment of PrP Sc resulting from proteinase K digestion of the first Ϸ88 residues. Prion rods possess the tinctorial properties of amyloid fibers (10,11) and resemble amyloid fibrils found in vivo (12).…”

mentioning

confidence: 99%

Evidence for assembly of prions with left-handed β-helices into trimers

Govaerts

Wille

Prusiner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

512

539

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Studies using low-resolution fiber diffraction, electron microscopy, and atomic force microscopy on various amyloid fibrils indicate that the misfolded conformers must be modular, compact, and adopt a cross-␤ structure. In an earlier study, we used electron crystallography to delineate molecular models of the N-terminally truncated, disease-causing isoform (PrP Sc ) of the prion protein, designated PrP 27-30, which polymerizes into amyloid fibrils, but we were unable to choose between a trimeric or hexameric arrangement of right-or left-handed ␤-helical models. From a study of 119 all-␤ folds observed in globular proteins, we have now determined that, if PrP Sc follows a known protein fold, it adopts either a ␤-sandwich or parallel ␤-helical architecture. With increasing evidence arguing for a parallel ␤-sheet organization in amyloids, we contend that the sequence of PrP is compatible with a parallel left-handed ␤-helical fold. Left-handed ␤-helices readily form trimers, providing a natural template for a trimeric model of PrP Sc . This trimeric model accommodates the PrP sequence from residues 89 -175 in a ␤-helical conformation with the C terminus (residues 176 -227), retaining the disulfide-linked ␣-helical conformation observed in the normal cellular isoform. In addition, the proposed model matches the structural constraints of the PrP 27-30 crystals, positioning residues 141-176 and the N-linked sugars appropriately. Our parallel left-handed ␤-helical model provides a coherent framework that is consistent with many structural, biochemical, immunological, and propagation features of prions. Moreover, the parallel left-handed ␤-helical model for PrP Sc may provide important clues to the structure of filaments found in some other neurodegenerative diseases.

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mentioning

confidence: 99%

Evidence for assembly of prions with left-handed β-helices into trimers

Govaerts

Wille

Prusiner

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

512

539

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“…Congo red dye demonstrated that the rods also fulfilled the tinctorial criteria for amyloid (107), and immunostaining later showed that PrP is a major component of amyloid plaques in some animals and humans with prion disease (118)(119)(120). Subsequently, it was recognized that the prion rods were not required for scrapie infectivity (121); furthermore, the rods were shown to be an artifact of purification during which limited proteolysis of PrP Sc generated PrP 27-30 that polymerized spontaneously in the presence of detergent ( Fig.…”

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confidence: 99%

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

137

138

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

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“…Subsequent to the removal of N-and C-terminal signal peptides, the mature form of mammalian PrP C contains residues 23-231 of a 253-amino acid sequence encoded by a single copy gene, Prnp (1). The C-terminal region of PrP C forms a globular structure comprising three ␣-helices and two short ␤-strands (2-4) and, during the process of prion infection, can re-fold into protease-resistant, ␤-sheet-enriched aggregates (5)(6)(7)(8)(9). In contrast, the N-terminal domain of PrP is highly flexible and typically includes five tandem copies of a conserved octapeptide repeat motif (3,4,6).…”

mentioning

confidence: 99%