Structures of amyloid fibrils formed by the prion protein derived peptides PrP(244–249) and PrP(245–250)

Yau, Jason; Sharpe, Simon

doi:10.1016/j.jsb.2012.08.002

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…The schematic shown in Figure 1 represents an N-terminal extension of a model depicted previously by Cobb & Surewicz (31). In the present model the entire region of residues ~90–220 refolds, eliminating all native α-helices consistent with prior observations (9, 144, 125). PrP Sc monomers stack along the fibril axis, forming stretches of parallel, in-register β-sheets.…”

Section: Prion Structuressupporting

confidence: 89%

“…These steric zippers can define distinct amyloid structures and help rationalize the propagation of distinct conformers or amyloid strains (see sidebar, Prion Strains and Amyloid Conformers). Steric zipper motifs occur in short stretches of different amyloid proteins (22, 144). They are proposed to stitch together specific sections of the proteins within amyloids to constrain the folding and assembly of newly recruited monomers during seeded/templated polymerization.…”

Section: Prion Structuresmentioning

confidence: 99%

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Prions and the Potential Transmissibility of Protein Misfolding Diseases

Kraus

Groveman

Caughey

2013

Annu. Rev. Microbiol.

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Prions, or infectious proteins, represent a major frontier in the study of infectious agents. The prions responsible for mammalian transmissible spongiform encephalopathies (TSEs) are due primarily to infectious self-propagation of misfolded prion proteins. TSE prion structures remain ill-defined, other than being highly structured, self-propagating, and often fibrillar protein multimers with the capacity to seed, or template, the conversion of their normal monomeric precursors into a pathogenic form. Purified TSE prions usually take the form of amyloid fibrils, which are self-seeding ultrastructures common to many serious protein misfolding diseases such as Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s (amytrophic lateral sclerosis). Indeed, recent reports have now provided evidence of prion-like propagation of several misfolded proteins from cell to cell, if not from tissue to tissue or individual to individual. These findings raise concerns that various protein misfolding diseases might have spreading, prion-like etiologies that contribute to pathogenesis or prevalence.

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Section: Prion Structuressupporting

confidence: 89%

Section: Prion Structuresmentioning

confidence: 99%

Prions and the Potential Transmissibility of Protein Misfolding Diseases

Kraus

Groveman

Caughey

2013

Annu. Rev. Microbiol.

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“…5C). The presence of more than one binding site is not surprising, as multiple peptides derived from PrP can be converted to an amyloid fibril with an in-register β-structure 54–57 . This fact implies that amyloid fibrils from full-length PrP contains multiple regions each having the ability to interact with monomeric PrP.…”

Section: Resultsmentioning

confidence: 99%

The native state of prion protein (PrP) directly inhibits formation of PrP-amyloid fibrils in vitro

Honda

Kuwata

2017

Sci Rep

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The conversion of globular proteins into amyloid fibrils is associated with a wide variety of human diseases. One example is the prion protein (PrP), which adopts an α-helical structure in the native state but its amyloid form is implicated in the pathogenesis of prion diseases. Previous evidence has suggested that destabilization of the native state promotes amyloid formation, but the underlying mechanism remains unknown. In this study, we report that the native state of PrP serves as a potent inhibitor in the formation of PrP amyloid fibrils. By monitoring the time courses of thioflavin T fluorescence, the kinetics of amyloid formation was studied in vitro under various concentrations of pre-formed amyloid, monomer, and denaturant. Quantitative analysis of the kinetic data using various models of enzyme kinetics suggested that the native state of PrP is either an uncompetitive or noncompetitive inhibitor of amyloid formation. This study highlights the significant role of the native state in inhibiting amyloid formation, which provides new insights into the pathogenesis of misfolding diseases.

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“…The group of Sharpe is particularly interested in the prion protein (PrP). They developed models for three fragments of this protein: PrP 106-126 , PrP 244-249 and PrP 245-250 (Walsh et al 2009;Yau and Sharpe 2012). PrP 106-126 is a peptide that shares many features with its parent protein, and is able to turn cellular PrP (PrP c ) into its scrapie form (PrP Sc ), and perhaps the best argument to study this peptide is the ability of monoclonal antibodies to recognize both fibrils formed by PrP 106-126 and PrP Sc fibrils (Jones et al 2009).…”

Section: Solid-state Nuclear Magnetic Resonance-ssnmrmentioning

confidence: 99%

Understanding amyloid fibril formation using protein fragments: structural investigations via vibrational spectroscopy and solid-state NMR

2018

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It is well established that amyloid proteins play a primary role in neurodegenerative diseases. Alzheimer's, Parkinson's, type II diabetes, and Creutzfeldt-Jakob's diseases are part of a wider family encompassing more than 50 human pathologies related to aggregation of proteins. Although this field of research is thoroughly investigated, several aspects of fibrillization remain misunderstood, which in turn slows down, or even impedes, advances in treating and curing amyloidoses. To solve this problem, several research groups have chosen to focus on short fragments of amyloid proteins, sequences that have been found to be of great importance for the amyloid formation process. Studying short peptides allows bypassing the complexity of working with full-length proteins and may provide important information relative to critical segments of amyloid proteins. To this end, efficient biophysical tools are required. In this review, we focus on two essential types of spectroscopic techniques, i.e., vibrational spectroscopy and its derivatives (conventional Raman scattering, deep-UV resonance Raman (DUVRR), Raman optical activity (ROA), surface-enhanced Raman spectroscopy (SERS), tip-enhanced Raman spectroscopy (TERS), infrared (IR) absorption spectroscopy, vibrational circular dichroism (VCD)) and solid-state nuclear magnetic resonance (ssNMR). These techniques revealed powerful to provide a better atomic and molecular comprehension of the amyloidogenic process and fibril structure. This review aims at underlining the information that these techniques can provide and at highlighting their strengths and weaknesses when studying amyloid fragments. Meaningful examples from the literature are provided for each technique, and their complementarity is stressed for the kinetic and structural characterization of amyloid fibril formation.

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Structures of amyloid fibrils formed by the prion protein derived peptides PrP(244–249) and PrP(245–250)

Cited by 8 publications

References 48 publications

Prions and the Potential Transmissibility of Protein Misfolding Diseases

Prions and the Potential Transmissibility of Protein Misfolding Diseases

The native state of prion protein (PrP) directly inhibits formation of PrP-amyloid fibrils in vitro

Understanding amyloid fibril formation using protein fragments: structural investigations via vibrational spectroscopy and solid-state NMR

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