The structure of the infectious prion protein

Requena, Jesús R.; Wille, Holger

doi:10.4161/pri.28368

Cited by 80 publications

(58 citation statements)

References 74 publications

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“…What do these findings bring to our knowledge in the context of the proposed PrP Sc structural models? For decades, the most popular model speculated that helices H2 and H3 were preserved in PrP Sc (8); however, recent works strongly suggest a complete absence of alpha-helical content in PrP Sc (3,22), and several authors have suggested that that a conformational change of the H2-H3 region, to which 193 to 197 residues belong, is essential to generate prions (4,6,49). The fact that the removal of the 193-197 region does not inhibit prion formation and appears to have little impact on their structure, as discussed above, led us to suggest that 193 to 197 amino acids are not likely to be inside a beta strand element essential for prion structure.…”

Section: Discussionmentioning

confidence: 99%

“…Recent works and reinterpretation of previously published FTIR data indicate that there is no more alpha-helical but high beta-sheet content in the protease-resistant fragment (3). This segment includes the three helices of the correctly folded PrP C , meaning that the whole domain undergoes drastic structural changes upon conversion (9,22). However, resolution of PrP Sc structure remains elusive, and little is known about the sequence and structural requirements for conversion of PrP C into prion.…”

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confidence: 99%

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Generating Bona Fide Mammalian Prions with Internal Deletions

Muñoz-Montesino

Sizun

Moudjou

et al. 2016

J Virol

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Mammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions. IMPORTANCEPrions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Generating Bona Fide Mammalian Prions with Internal Deletions

Muñoz-Montesino

Sizun

Moudjou

et al. 2016

J Virol

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“…Values for a-helical contributions are not compared because FTIRand CD-based data have been criticized recently not to support the presence of residual a-helices in PrP Sc and PrP27-30. 46 (v) A sequentially assigned minimum of 3 consecutive b-sheet residues or 4 consecutive a-helical residues are required to define a b-strand or an a-helix, respectively, at a distinct sequence position. 47 Although we lack site-specific assignments, we found some hints for the position of secondary structure elements by combining the secondary structure information for individual amino acid types which information about the primary sequence.…”

Section: Secondary Structure Distribution Comparison Of Amyloid Typementioning

confidence: 99%

Progress towards structural understanding of infectious sheep PrP-amyloid

Müller

Brener

Andréoletti

et al. 2014

Prion

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The still elusive structural difference of non-infectious and infectious amyloid of the mammalian prion protein (PrP) is a major pending milestone in understanding protein-mediated infectivity in neurodegenerative diseases. Preparations of PrP-amyloid proven to be infectious have never been investigated with a high-resolution technique. All available models to date have been based on low-resolution data. Here, we establish protocols for the preparation of infectious samples of full-length recombinant (rec) PrP-amyloid in NMR-sufficient amounts by spontaneous fibrillation and seeded fibril growth from brain extract. We link biological and structural data of infectious recPrP-amyloid, derived from bioassays, atomic force microscopy, and solid-state NMR spectroscopy. Our data indicate a semi-mobile N-terminus, some residues with secondary chemical shifts typical of a-helical secondary structure in the middle part between »115 to »155, and a distinct b-sheet core C-terminal of residue »155. These findings are not in agreement with all current models for PrP-amyloid. We also provide evidence that samples seeded from brain extract may not differ in the overall arrangement of secondary structure elements, but rather in the flexibility of protein segments outside the b-core region. Taken together, our protocols provide an essential basis for the high-resolution characterization of non-infectious and infectious PrP-amyloid in the near future.

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“…PrP Sc is structurally polydisperse and hence is difficult to crystallize. Although numerous models have been suggested, the definitive structure of PrP Sc has not yet been elucidated, given its proclivity to aggregate; moreover, current models have been discordant with experimental data (87).…”

Section: Prions and Diverse Strains Prionsmentioning

confidence: 99%

Prions: Beyond a Single Protein

Das

Zou

2016

Clin Microbiol Rev

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SUMMARYSince the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a “prion.” Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins—not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease.

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The structure of the infectious prion protein

Cited by 80 publications

References 74 publications

Generating Bona Fide Mammalian Prions with Internal Deletions

Generating Bona Fide Mammalian Prions with Internal Deletions

Progress towards structural understanding of infectious sheep PrP-amyloid

Prions: Beyond a Single Protein

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