Alternative Prion Structural Changes Revealed by High Pressure

Torrent, Joan; Alvarez-Martinez, Maria Teresa; Heitz, Fréderic; Liautard, Jean‐Pierre; Balny, Claude; Lange, Reinhard

doi:10.1021/bi0269916

Cited by 86 publications

(79 citation statements)

References 53 publications

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“…About 30% of amyloid fibrils became dissociated into soluble species, whereas the remaining fibrils stayed in fibrillar form but lost some of the amyloid-specific features. High pressure refolding of temperature-induced ␤-sheetrich aggregates of a mammalian prion protein has been previously reported (55,56). However, to our knowledge, none of the ␤-sheet-rich misfolded conformers was described to display amyloid fibril structure.…”

Section: Discussionmentioning

confidence: 81%

“…We, thus, suggest that pressurized fibrils should be considered as a new alternative conformation that can be reached by a protein under certain physicochemical conditions. Indeed, previous insight into unexplored conformational states of the recombinant cellular PrP isoform was obtained using high pressure (55,56,(62)(63)(64)(65)(66). The results revealed that these PrP states are distinguished by their volumetric properties (i.e.…”

Section: Discussionmentioning

confidence: 98%

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Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Moustaine

Perrier

et al. 2011

Journal of Biological Chemistry

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Prion proteins (PrP) can aggregate into toxic and possibly infectious amyloid fibrils. This particular macrostructure confers on them an extreme and still unexplained stability. To provide mechanistic insights into this self-assembly process, we used high pressure as a thermodynamic tool for perturbing the structure of mature amyloid fibrils that were prepared from recombinant full-length mouse PrP. Application of high pressure led to irreversible loss of several specific amyloid features, such as thioflavin T and 8-anilino-1-naphthalene sulfonate binding, alteration of the characteristic proteinase K digestion pattern, and a significant decrease in the ␤-sheet structure and cytotoxicity of amyloid fibrils. Partial disaggregation of the mature fibrils into monomeric soluble PrP was observed. The remaining amyloid fibrils underwent a change in secondary structure that led to morphologically different fibrils composed of a reduced number of proto-filaments. The kinetics of these reactions was studied by recording the pressure-induced dissociation of thioflavin T from the amyloid fibrils. Analysis of the pressure and temperature dependence of the relaxation rates revealed partly unstructured and hydrated kinetic transition states and highlighted the importance of collapsing and hydrating inter-and intramolecular cavities to overcome the high free energy barrier that stabilizes amyloid fibrils.Amyloid fibrils are filamentous polypeptide aggregates that are associated with devastating disorders such as Alzheimer and Parkinson diseases, type II diabetes, and prion (proteinaceous infectious particle) diseases, including Creutzfeldt-Jakob and mad cow disease (1, 2). There is increasing evidence that under appropriate conditions the amyloid state is accessible also to many other proteins that are not related to diseases, suggesting that the amyloid state is a generic structural feature, which might be adopted by any polypeptide chain (3-6).The development of in vitro model systems together with various biophysical and biochemical techniques (7-9) has improved the knowledge on the physicochemical basis of amyloid formation as well as on their structural and biochemical properties. It is now well recognized that a common property of amyloid fibrils is the extensive stacking of intermolecular ␤-strands that are arranged perpendicularly to the fibril axis and stabilized by a dense network of non-covalent interactions (10 -13). These fibrils consist of a variable number and arrangement of thin assemblies called proto-filaments that give rise to different fibril morphologies of diameters between 5 and 30 nanometers, both in in vitro preparations or in tissues (14 -22). Fibrils and their precursors are generally cytotoxic (23, 24) and are, thus, thought to be responsible for the neurodegeneration that is associated with many amyloid diseases.Yet the fundamental parameters that govern the protein aggregation process and dictate fibril stability/clearance are not well known. As the study of protein folding has been greatly advanc...

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Moustaine

Perrier

et al. 2011

Journal of Biological Chemistry

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“…This apparent discrepancy with the present study could be explained if the PK-resistant 35 SPrP products represent folding intermediates (and not bona fide PrP Sc ) that are capable of reversing to PK-sensitive 35 SPrP molecules. Other reports that analyzed recombinant prion protein aggregation into ␤-sheet-rich structures were able to demonstrate a reversion to the original ␣-helical structure under certain conditions (29,30). These studies suggest that there are folding intermediates in the transition from PrP C to PrP Sc .…”

Section: Fig 4 Prpmentioning

confidence: 74%

Strain-specific Kinetics of Prion Protein Formation in Vitro and in Vivo

Mulcahy¹,

Bessen

2004

Journal of Biological Chemistry

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The molecular basis of prion strain diversity is proposed to be encoded by distinct conformations of the abnormal scrapie isoform of the prion protein (PrP Sc ). PrP Sc formation for the hyper (HY) and drowsy (DY) strains of the transmissible mink encephalopathy (TME) agent was investigated using the cell-free PrP conversion reaction to determine the role of distinct PrP Sc conformations in the rate of in vitro conversion of cellular PrP into protease-resistant PrP. PrP conversion increased at an exponential rate for both TME strains until peak levels were reached at 72-96 h of reaction time. The amount and rate of PrP conversion for HY TME was greater than those for DY TME between 48 h and the peak level of PrP conversion. Between 96 and 120 h, there was a negative rate of PrP conversion; and between 120 and 168 h, the net rate of HY and DY PrP conversion approached zero. These findings suggest that PrP conversion can occur in three distinct stages: an elongation phase, a depolymerization phase, and a steady-state phase. Strain-specific properties between the TME strains were identified only during the elongation phase. The steady-state phase could be disrupted by the addition of PrP Sc to, or by sonication of, the cell-free PrP conversion reaction. These treatments resulted in an increase in the amount of PrP conversion that was equal to or greater than that found during the peak level of PrP conversion for both TME strains, indicating that the steadystate phase was in dynamic equilibrium. In a related study, the rate of accumulation of HY and DY PrP Sc in hamster brain exhibited a strain-specific pattern that had similarities to the strain-specific PrP conversion reaction during the elongation phase. These results suggest that strain-specific conformations of PrP Sc have the ability to influence the rate of additional PrP Sc formation from cellular PrP both in vitro and in vivo.

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“…This appears to be caused by an aberrant conformational change of the cellular PrP, leading to its deposition in the form of amyloid fibrils. Recently, we have shown that using high-pressure perturbation, recombinant PrP can be converted to different novel misfolded conformers (13)(14)(15). By a judicious choice of pressure, temperature, pH, and incubation time, it is possible to attain several distinct PrP structures.…”

Section: Pressure Effects On Tertiary Structure: the Case Of Prion Prmentioning

confidence: 99%

The powerful high pressure tool for protein conformational studies

Marchal

Torrent

Masson

et al. 2005

Braz J Med Biol Res

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The pressure behavior of proteins may be summarized as a the pressure-induced disordering of their structures. This thermodynamic parameter has effects on proteins that are similar but not identical to those induced by temperature, the other thermodynamic parameter. Of particular importance are the intermolecular interactions that follow partial protein unfolding and that give rise to the formation of fibrils. Because some proteins do not form fibrils under pressure, these observations can be related to the shape of the stability diagram. Weak interactions which are differently affected by hydrostatic pressure or temperature play a determinant role in protein stability. Pressure acts on the 2º, 3º and 4º structures of proteins which are maintained by electrostatic and hydrophobic interactions and by hydrogen bonds. We present some typical examples of how pressure affects the tertiary structure of proteins (the case of prion proteins), induces unfolding (ataxin), is a convenient tool to study enzyme dissociation (enolase), and provides arguments to understand the role of the partial volume of an enzyme (butyrylcholinesterase). This approach may have important implications for the understanding of the basic mechanism of protein diseases and for the development of preventive and therapeutic measures.

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Alternative Prion Structural Changes Revealed by High Pressure

Cited by 86 publications

References 53 publications

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure

Strain-specific Kinetics of Prion Protein Formation in Vitro and in Vivo

The powerful high pressure tool for protein conformational studies

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