Conformational polymorphism of wild‐type and mutant prion proteins: Energy landscape analysis

Levy, Yaakov; Becker, Oren M.

doi:10.1002/prot.10095

Cited by 34 publications

(14 citation statements)

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“…So far, our knowledge of PrP Sc characteristics in gCJD originates from studies using brain material. Accordingly, in E200K or V210I mutation carriers, the disease is caused by an altered structure of PrP C [ 19 ] and the metabolism of PrP is different during life [ 20 ]. These conformational changes might engender its conversion into PrP Sc by affecting the interactions with other cellular partners or the fibrillation process of PrP [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Characteristic CSF Prion Seeding Efficiency in Humans with Prion Diseases

et al. 2014

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The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrPSc) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrPSc type, and other disease-related factors on the real-time quaking-induced conversion (RT-QuIC) response. We analyzed times to 10,000 relative fluorescence units, areas under the curve and the signal maximum of RT-QuIC response as seeding parameters of interest. Interestingly, type of prion disease (sporadic vs. genetic) and the PRNP mutation (E200K vs. V210I and FFI), codon 129 genotype, and PrPSc type affected RT-QuIC response. In genetic forms, type of mutation showed the strongest effect on the observed outcome variables. In sporadic CJD, MM1 patients displayed a higher RT-QuIC signal maximum compared to MV1 and VV1. Age and gender were not associated with RT-QuIC signal, but patients with a short disease course showed a higher seeding efficiency of the RT-QuIC response. This study demonstrated that PrPSc characteristics in the CSF of human prion disease patients are associated with disease subtypes and rate of decline as defined by disease duration.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-014-8709-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Characteristic CSF Prion Seeding Efficiency in Humans with Prion Diseases

et al. 2014

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“…Previous conformational studies indicate that a transition from α-helical to β-sheet structures (PrP C PrP Sc ) is likely to be the crucial event in prion propagation [31,32,33,34,35]. To investigate which portions of the native protein sequence are involved in the conformational transition from PrP C to PrP Sc and PrP amyloid, several groups have analyzed the secondary structures and fibrillogenic properties of synthetic PrP peptides [36].…”

Section: Introductionmentioning

confidence: 99%

Solvent Microenvironments and Copper Binding Alters the Conformation and Toxicity of a Prion Fragment

et al. 2013

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The secondary structures of amyloidogenic proteins are largely influenced by various intra and extra cellular microenvironments and metal ions that govern cytotoxicity. The secondary structure of a prion fragment, PrP(111-126), was determined using circular dichroism (CD) spectroscopy in various microenvironments. The conformational preferences of the prion peptide fragment were examined by changing solvent conditions and pH, and by introducing external stress (sonication). These physical and chemical environments simulate various cellular components at the water-membrane interface, namely differing aqueous environments and metal chelating ions. The results show that PrP(111-126) adopts different conformations in assembled and non-assembled forms. Aging studies on the PrP(111-126) peptide fragment in aqueous buffer demonstrated a structural transition from random coil to a stable β-sheet structure. A similar, but significantly accelerated structural transition was observed upon sonication in aqueous environment. With increasing TFE concentrations, the helical content of PrP(111-126) increased persistently during the structural transition process from random coil. In aqueous SDS solution, PrP(111-126) exhibited β-sheet conformation with greater α-helical content. No significant conformational changes were observed under various pH conditions. Addition of Cu2+ ions inhibited the structural transition and fibril formation of the peptide in a cell free in vitro system. The fact that Cu2+ supplementation attenuates the fibrillar assemblies and cytotoxicity of PrP(111-126) was witnessed through structural morphology studies using AFM as well as cytotoxicity using MTT measurements. We observed negligible effects during both physical and chemical stimulation on conformation of the prion fragment in the presence of Cu2+ ions. The toxicity of PrP(111-126) to cultured astrocytes was reduced following the addition of Cu2+ ions, owing to binding affinity of copper towards histidine moiety present in the peptide.

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“…However, the dynamic details of structural transition need novel methods to probe the solution state structure of prion peptide fragments using spectroscopic techniques. Early conforma-tional studies have indicated that a transition from a-helical to b-sheet structure (PrP c -PrP Sc ) is likely to be the crucial event in prion propagation (Pan et al, 1993;Prusiner, 1998;Prusiner et al, 1998;Petchanikow et al, 2001;Levy and Becker, 2002). To investigate which amino acid sequences feature in the conformational transition from PrP c to PrP Sc and PrP amyloid, several groups have analyzed the secondary structure and fibrillogenic properties of synthetic peptides of PrP (Baldwin et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Conformational Polymorphism of the Amyloidogenic Peptide Homologous to Residues 113–127 of the Prion Protein

Satheeshkumar

Jayakumar

2003

Biophysical Journal

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Conformational transitions are thought to be the prime mechanism of amyloid formation in prion diseases. The prion proteins are known to exhibit polymorphic behavior that explains their ability of "conformation switching" facilitated by structured "seeds" consisting of transformed proteins. Oligopeptides containing prion sequences showing the polymorphism are not known even though amyloid formation is observed in these fragments. In this work, we have observed polymorphism in a 15-residue peptide PrP (113-127) that is known to form amyloid fibrils on aging. To see the polymorphic behavior of this peptide in different solvent environments, circular dichroism (CD) spectroscopic studies on an aqueous solution of PrP (113-127) in different trifluoroethanol (TFE) concentrations were carried out. The results show that PrP (113-127) have sheet preference in lower TFE concentration whereas it has more helical conformation in higher TFE content (>40%). The structural transitions involved in TFE solvent were studied using interval-scan CD and FT-IR studies. It is interesting to note that the alpha-helical structure persists throughout the structural transition process involved in amyloid fibril formation implicating the involvement of both N- and C-terminal sequences. To unravel the role of the N-terminal region in the polymorphism of the PrP (113-127), CD studies on another synthetic peptide, PrP (113-120) were carried out. PrP(113-120) exhibits random coil conformation in 100% water and helical conformation in 100% TFE, indicating the importance of full-length sequence for beta-sheet formation. Besides, the influence of different chemico-physical conditions such as concentration, pH, ionic strength, and membrane like environment on the secondary structure of the peptide PrP (113-127) has been investigated. At higher concentration, PrP (113-127) shows features of sheet conformation even in 100% TFE suggesting aggregation. In the presence of 5% solution of sodium dodecyl sulfate, PrP (113-127) takes high alpha-helical propensity. The environment-dependent conformational polymorphism of PrP (113-127) and its marked tendency to form stable beta-sheet structure at acidic pH could account for its conformation switching behavior from alpha-helix to beta-sheet. This work emphasizes the coordinative involvement of N-terminal and C-terminal sequences in the self-assembly of PrP (113-127).

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Conformational polymorphism of wild‐type and mutant prion proteins: Energy landscape analysis

Cited by 34 publications

References 59 publications

Characteristic CSF Prion Seeding Efficiency in Humans with Prion Diseases

Characteristic CSF Prion Seeding Efficiency in Humans with Prion Diseases

Solvent Microenvironments and Copper Binding Alters the Conformation and Toxicity of a Prion Fragment

Conformational Polymorphism of the Amyloidogenic Peptide Homologous to Residues 113–127 of the Prion Protein

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