Acid-induced Molten Globule State of a Prion Protein

Honda, Ryo; Yamaguchi, Keiichi; Kuwata, Kazuo

doi:10.1074/jbc.m114.559450

Cited by 43 publications

(16 citation statements)

References 46 publications

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“…The 13 Cα-chemical shift indices at pH 2.0 obtained by sequentially assigning the peaks in the NMR spectrum (Figure S1) exhibit values near zero in the S1-H1-H2 segment (amino acid residue: 129–160) (Figure 1E & F). This shows that this segment is almost completely unfolded in the A-state (Wishart et al, 1992), which is consistent with previous hydrogen/deuterium exchange results (Honda et al, 2014). In contrast, most of the H2-H3 segment remains unassigned due to severe line broadening (Figure S1), which suggests that this region fluctuates between some folded and unfolded structures on the millisecond time scale.…”

Section: Resultssupporting

confidence: 92%

“…In contrast, most of the H2-H3 segment remains unassigned due to severe line broadening (Figure S1), which suggests that this region fluctuates between some folded and unfolded structures on the millisecond time scale. Thus, the N-terminal S1-H1-S2 segment appears to be extensively disordered or completely unfolded in the A-state, while the C-terminal H2-H3 segment retains a marginally stable structure (Honda et al, 2014). …”

Section: Resultsmentioning

confidence: 99%

“…We recently reported the formation of an acid-induced partially unfolded state characterized by the molten globule-like structure (A-state) just prior to the formation of β-rich oligomers (Honda et al, 2014). The initial fraction of PrP in the A-state was strongly correlated with the rate of oligomerization at pH 2-5, suggesting that the A-state is directly involved in the oligomerization pathway.…”

Section: Introductionmentioning

confidence: 99%

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A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein

Honda

Yamaguchi

et al. 2015

Structure

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SUMMARY Transient folding intermediates and/or partially unfolded equilibrium states are thought to play a key role in the formation of protein aggregates. However, there is only indirect evidence linking accumulation of folding intermediates to aggregation, and the underlying mechanism remains to be elucidated. Here we show that a partially unfolded state of the prion protein accumulates both as a stable equilibrium state at acidic pH (A-state) and as a late folding intermediate. With a time resolution of approximately 60 μs, we systematically studied the kinetics of folding and unfolding, starting from various initial conditions including the U-, N-, and A-states. Quantitative modeling showed that the observed kinetic data are completely consistent with a sequential four-state mechanism where the A-state is a late folding intermediate. Combined with previous evidence linking A-state accumulation to aggregation, the results indicate that this native-like state serves as a branching point between the folding and aggregation pathways.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein

Honda

Yamaguchi

et al. 2015

Structure

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“…Subsequent study then focused on the identification of folding intermediates using a variety of approaches that all showed that the C-terminal portion of the prion protein folded more rapidly [22,23]. Investigation into pre-oligomer structures also showed the presence of an acid-induced molten globule state where the C-terminal region remained folded but under physiologic conditions an equilibrium intermediate is not detected [24]. Native state hydrogen exchange experiments monitored by NMR indicated that the C-terminal region was more stable than the N-terminal region [25].…”

Section: Discussionmentioning

confidence: 99%

“…An undetected intermediate in the urea denaturation would result in an underestimation of the global stability. However, efforts to detect such an intermediate found no evidence [24] leaving structure in the denatured state the most suitable explanation. To determine if residual structure in the denatured state of bovine prion protein could explain the enhanced disease of bPrP E211K variants, we investigated the thermodynamic parameters describing the unfolding of bPrP wild type and E211K proteins with the first observation being that the E211K mutation gave a total decrease in stability of 1.62 kcal mol −1 , and a melting temperature 2.8 °C lower than the wild-type protein.…”

Section: Discussionmentioning

confidence: 99%

Thermodynamic characterization for the denatured state of bovine prion protein and the BSE Associated variant E211K

Hwang

Nicholson

2018

Prion

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Propagation of transmissible spongiform encephalopathies involves the conversion of cellular prion protein, PrPC, into a misfolded oligomeric form, PrPSc. The most common hereditary prion disease is a genetic form of Creutzfeldt-Jakob disease in humans, in which a mutation in the prion gene results in a glutamic acid to lysine substitution at position 200 (E200K) in PrP. In cattle, the analogous amino acid substitution is found at residue 211 (E211K) and has been associated with a case of bovine spongiform encephalopathy. Here, we have compared the secondary structure of E211K to that of wild type using circular dichroism and completed a thermodynamic analysis of the folding of recombinant wild type and E211K variants of the bovine prion protein. The secondary structure of the E211K variant was essentially indistinguishable from that of wild type. The thermodynamic stability of E211K substitution showed a slight destabilization relative to the wild type consistent with results reported for recombinant human prion protein and its mutant E200K. In addition, the E211K variant exhibits a similarly compact denatured state to that of wild type based upon similar m-value and change in heat capacity of unfolding for the proteins. Together these results indicate that residual structure in the denatured state of bPrP is present in both the wild type protein and BSE associated variant E211K. Given this observation, as well as folding similarities reported for other disease associated variants of PrP it is worth consideration that functional aspects of PrP conformation may play a role in the misfolding process.

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Structural Effects of Multiple Pathogenic Mutations Suggest a Model for the Initiation of Misfolding of the Prion Protein

Singh

Udgaonkar

2015

Angewandte Chemie

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Am olecular understanding of the prion diseases requires delineation of the origin of misfolding of the prion protein (PrP). An understanding of howd ifferent diseaselinked mutations affect the structure and dynamics of native monomeric PrP can provideaclue about howm isfolding commences.Inthis study,hydrogen-deuterium exchange mass spectrometry was used to showt hat several disease-linked mutant variants,w hicha re thermodynamically destabilized, share ac ommon structural perturbation in their native states: helix 1isdestabilizedtoane xtent that correlates well with the destabilization of the native protein. The mutant variants misfold and form oligomers faster than does the wild-type protein, at rates that increase exponentially with the extent to which helix 1i sd estabilizedi nt he native protein. It appears, therefore,that the loss of helix 1structure marks the beginning of PrP misfolding and oligomerization.

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Acid-induced Molten Globule State of a Prion Protein

Cited by 43 publications

References 46 publications

A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein

A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein

Thermodynamic characterization for the denatured state of bovine prion protein and the BSE Associated variant E211K

Structural Effects of Multiple Pathogenic Mutations Suggest a Model for the Initiation of Misfolding of the Prion Protein

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