Conformational Properties of β-PrP

Hosszu, Laszlo L. P.; Trevitt, Clare R.; Jones, Samanthan; Batchelor, Mark; Scott, David J.; Jackson, Graham S.; Collinge, John; Waltho, Jonathan P.; Clarke, Anthony R.

doi:10.1074/jbc.m809173200

Cited by 33 publications

(48 citation statements)

References 82 publications

(119 reference statements)

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“…The deconvoluted peak (see insets) derived from each sample corresponded to the predicted molecular mass of oxidized SHaPrP(90-231), 16,240 Da. This is considered to be more biologically relevant than its reduced counterpart [3,43]. This is because the oxidized construct is structured due to the presence of a disulphide bond.…”

Section: Resultsmentioning

confidence: 97%

Structural analysis of prion proteins by means of drift cell and traveling wave ion mobility mass spectrometry

Hilton

Thalassinos

Grabenauer

et al. 2010

J. Am. Soc. Mass Spectrom.

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The prion protein (PrP) is implicitly involved in the pathogenesis of transmissible spongiform encephalopathies (TSEs). The conversion of normal cellular PrP (PrP(C)), a protein that is predominantly alpha-helical, to a beta-sheet-rich isoform (PrP(Sc)), which has a propensity to aggregate, is the key molecular event in prion diseases. During its short life span, PrP can experience two different pH environments; a mildly acidic environment, whilst cycling within the cell, and a neutral pH when it is glycosyl phosphatidylinositol (GPI)-anchored to the cell membrane. Ion mobility (IM) combined with mass spectrometry has been employed to differentiate between two conformational isoforms of recombinant Syrian hamster prion protein (SHaPrP). The recombinant proteins studied were alpha-helical SHaPrP(90-231) and beta-sheet-rich SHaPrP(90-231) at pH 5.5 and pH 7.0. The recombinant proteins have the same nominal mass-to-charge ratio (m/z) but differ in their secondary and tertiary structures. A comparison of traveling-wave (T-Wave) ion mobility and drift cell ion mobility (DCIM) mass spectrometry estimated and absolute cross-sections showed an excellent agreement between the two techniques. The use of T-Wave ion mobility as a shape-selective separation technique enabled differentiation between the estimated cross-sections and arrival time distributions (ATDs) of alpha-helical SHaPrP(90-231) and beta-sheet-rich SHaPrP(90-231) at pH 5.5. No differences in cross-section or ATD profiles were observed between the protein isoforms at pH 7.0. The findings have potential implications for a new ante-mortem screening assay, in bodily fluids, for prion misfolding diseases such as TSEs.

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Section: Resultsmentioning

confidence: 97%

Structural analysis of prion proteins by means of drift cell and traveling wave ion mobility mass spectrometry

Hilton

Thalassinos

Grabenauer

et al. 2010

J. Am. Soc. Mass Spectrom.

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“…Significant amounts of b-structure have been detected in oligomers of prion protein (PrP) [90,91]. PrP oligomers formed at low pH were b-sheet rich and had lower stability and lower extent of b-structure compared to fibrils [90,92,93]. These oligomers were not on the pathway for fibril formation.…”

Section: Other Proteinsmentioning

confidence: 99%

Structural, morphological, and functional diversity of amyloid oligomers

2015

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a b s t r a c tProtein misfolding and aggregation are known to play a crucial role in a number of important human diseases (Alzheimer's, Parkinson's, prion, diabetes, cataracts, etc.) as well as in a multitude of physiological processes. Protein aggregation is a highly complex process resulting in a variety of aggregates with different structures and morphologies. Oligomeric protein aggregates (amyloid oligomers) are formed as both intermediates and final products of the aggregation process. They are believed to play an important role in many protein aggregation-related diseases, and many of them are highly cytotoxic. Due to their instability and structural heterogeneity, information about structure, mechanism of formation, and physiological effects of amyloid oligomers is sparse. This review attempts to summarize the existing information on the major properties of amyloid oligomers.

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“…Previous studies had suggested the protein formed a molten globule at low pH (55)(56)(57)(58). Surprisingly, at pH 4.4, the Trp triplet decays remain single-exponential even at 0 M GdnHCl, suggesting the protein is freely diffusing and there is no stable structure.…”

Section: Resultsmentioning

confidence: 88%

Prion protein dynamics before aggregation

Srivastava

Lapidus

2017

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

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Prion diseases, like Alzheimer's disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and accumulation of protein deposits in neuronal cells. Here we measure intramolecular polypeptide backbone reconfiguration as a way to understand the molecular basis of prion aggregation. Our hypothesis is that when reconfiguration is either much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. Using the technique of Trp-Cys contact quenching, we investigate the effects of various conditions on reconfiguration dynamics of the Syrian hamster and rabbit prion proteins. This protein exhibits behavior in all three reconfiguration regimes. We conclude that the hamster prion is prone to aggregation at pH 4.4 because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs, whereas the rabbit sequence avoids aggregation by reconfiguring 10 times faster than the hamster sequence.protein folding | protein aggregation | intramolecular diffusion | prion disease | astemizole P rion disease, also known as transmissible spongiform encephalopathy (TSE) is attributed to misfolding followed by ordered aggregation and accumulation of protein deposits in neuronal cells (1-3). According to the "protein-only" hypothesis, the central event in prion (PrP) pathogenesis is the conformational conversion of the cellular α-helical rich isoform, PrP C , into misfolded β-sheet rich isoform, PrP Sc (3-6). The infectious form PrP Sc is believed to catalyze the conversion of PrP C , thereby permitting transmission between individuals and species (3, 7-10). However, there is very little known about PrP C before ordered aggregation. No putative aggregation precursor structure has been definitively identified; the protein may even be completely unstructured. It is believed that PrP C repeatedly cycles between the cell surface (∼pH 7.0) and endocytic compartment that has a pH as low as 4. 4 (11, 12). Aggregated prion has been isolated from this compartment so it has been suggested that aggregation initiates in late endosomes (13,14). Also, the reduction of the disulfide bridge has been reported to augment misfolding in vitro and may play a significant role in prion pathogenesis (15)(16)(17)(18)(19)(20). However, the physical basis for aggregation of prion, particularly under certain solvent conditions, is still poorly understood.Protein folding is a diffusive search of the unfolded polypeptide chain over the energy landscape in conformational space for a minimum energy state (21). Intramolecular diffusion (diffusion of one part of the chain relative to another) plays a critical role by determining the rate at which an unfolded polypeptide chain finds its native state (22-25). It has been measured for various peptides and pro...

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Conformational Properties of β-PrP

Cited by 33 publications

References 82 publications

Structural analysis of prion proteins by means of drift cell and traveling wave ion mobility mass spectrometry

Structural analysis of prion proteins by means of drift cell and traveling wave ion mobility mass spectrometry

Structural, morphological, and functional diversity of amyloid oligomers

Prion protein dynamics before aggregation

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