Prion Protein Aggregation Induced by Copper(II) and Heparan Sulfate. Pressure-dependent Switch of Reaction Pathways

2008 ◽  
Vol 63 (6) ◽  
pp. 747-755 ◽  
Author(s):  
Driss El Moustaine ◽  
Joan Torrent ◽  
Reinhard Lange
Keyword(s):  
Heparan Sulfate ◽  
Prion Protein ◽  
Conformational Changes ◽  
Atmospheric Pressure ◽  
Amyloid Fibrils ◽  
Copper Ions ◽  
Fibril Formation ◽  
Cellular Prion Protein ◽  
Reaction Pathways ◽  
Structural Alterations

Copper ions (Cu2+) and heparan sulfate (HS) are suspected to act as regulatory agents in the conversion of cellular prion protein (PrPC) to its infectious isoform. However, the mechanism of this reaction is still largely unknown. Our previous report suggested multidimensional pathways for structural alterations of PrP, which may be modulated by high pressure (HP). Here we use HP to investigate the effects of Cu2+ and HS binding on PrP conformational changes and assembly. In the presence of Cu2+, amyloid fibrils are formed only under HP. In contrast, in the presence of HS, fibrils are formed at atmospheric pressure, but not under HP. Both compounds appear to compete for the same binding site, since HS-supported fibril formation is quenched by Cu2+. Inversely, Cu2+- mediated fibril formation under HP is inhibited by HS.

scholarly journals Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106–126

1999 ◽  
Vol 342 (1) ◽  
pp. 207-214 ◽  
Author(s):  
Mario SALMONA ◽  
Paolo MALESANI ◽  
Luca DE GIOIA ◽  
Stefano GORLA ◽  
Maurizio BRUSCHI ◽  
...  
Keyword(s):  
Prion Protein ◽  
Conformational Changes ◽  
Amyloid Fibrils ◽  
Physicochemical Characteristics ◽  
Cellular Prion Protein ◽  
Random Coil ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
C Terminus ◽  
Molecular Determinants

Prion diseases are marked by the cerebral accumulation of conformationally modified forms of the cellular prion protein (PrPC), known as PrPres. The region comprising the residues 106-126 of human PrP seems to have a key role in this conformational conversion, because a synthetic peptide homologous with this sequence (PrP106-126) adopts different secondary structures in different environments. To investigate the molecular determinants of the physicochemical characteristics of PrP106-126, we synthesized a series of analogues including PrP106-126 HD, PrP106-126 A and PrP106-126 K, with L-His → D-His, His → Ala and His → Lys substitutions respectively at position 111, PrP106-126 NH2 with amidation of the C-terminus, PrP106-126 V with an Ala → Val substition at position 117, and PrP106-126 VNH2 with an Ala → Val substitution at position 117 and amidation of the C-terminus. The analysis of the secondary structure and aggregation properties of PrP106-126 and its analogues showed the following. (1) His111 is central to the conformational changes of PrP peptides. (2) Amidation of the C-terminal Gly126 yields a predominantly random coil structure, abolishes the molecular polymorphism and decreases the propensity of PrP106-126 to generate amyloid fibrils. (3) PrP106-126 V, carrying an Ala → Val substitution at position 117, does not demonstrate a fibrillogenic ability superior to that of PrP106-126. However, the presence of Val at position 117 increases the aggregation properties of the amidated peptide. (4) Amyloid fibrils are not required for neurotoxicity because the effects of PrP106-126 NH2 on primary neuronal cultures were similar to those of the wild-type sequence. Conversely, astroglial proliferation is related to the presence of amyloid fibrils, suggesting that astrogliosis in prion encephalopathies without amyloid deposits is a mediated effect rather than a direct effect of disease-specific PrP isoforms.

scholarly journals Differential modulation of NMDA and AMPA receptors by cellular prion protein and copper ions

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Sun Huang ◽  
Lina Chen ◽  
Chris Bladen ◽  
Peter K. Stys ◽  
Gerald W. Zamponi
Keyword(s):  
Prion Protein ◽  
Ampa Receptors ◽  
Copper Ions ◽  
Cellular Prion Protein ◽  
Differential Modulation

scholarly journals The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

2020 ◽  
Vol 155 (5) ◽  
pp. 577-591 ◽  
Author(s):  
Elena De Cecco ◽  
Luigi Celauro ◽  
Silvia Vanni ◽  
Micaela Grandolfo ◽  
Edoardo Bistaffa ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Cellular Prion Protein ◽  
Prion Propagation

scholarly journals Identification of the Heparan Sulfate Binding Sites in the Cellular Prion Protein

2002 ◽  
Vol 277 (21) ◽  
pp. 18421-18430 ◽  
Author(s):  
Richard G. Warner ◽  
Christoph Hundt ◽  
Stefan Weiss ◽  
Jeremy E. Turnbull
Keyword(s):  
Heparan Sulfate ◽  
Prion Protein ◽  
Binding Sites ◽  
Cellular Prion Protein

scholarly journals The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

2020 ◽  
Author(s):  
Elena De Cecco ◽  
Luigi Celauro ◽  
Silvia Vanni ◽  
Micaela Grandolfo ◽  
Adriano Aguzzi ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Brain Diseases ◽  
Gene Encoding ◽  
Prion Propagation ◽  
Prion Conversion ◽  
Tau Fibrils

AbstractTauopathies are prevalent, invariably fatal brain diseases for which no cure is available. Tauopathies progressively affect the brain through cell-to-cell transfer of tau protein amyloids, yet the spreading mechanisms are unknown. Here we show that the cellular prion protein (PrPC) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, we found that tau amyloids bind to PrPC; internalization of tau fibrils was reduced in isogenic cells devoid of the gene encoding PrPC. Antibodies against N-proximal epitopes of PrPC impaired the binding of tau amyloids and decreased their uptake. Surprisingly, exposure of chronically prion-infected cells to tau amyloids reduced the accumulation of aggregated prion protein; this effect lasted for more than 72 hours after amyloid removal. These results point to bidirectional interactions between the two proteins: whilst PrPC mediates the entrance of tau fibrils in cells, PrPSc buildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.

scholarly journals Nigella Sativa : A Potential Inhibitor for Insulin Fibril Formation

2020 ◽  
Vol 11 (1) ◽  
pp. 765-774
Author(s):  
Sandhya A ◽  
Gomathi Kanayiram ◽  
Kiruthika L ◽  
Aafreen Afroz S
Keyword(s):  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Type Ii Diabetes ◽  
Amyloid Fibrils ◽  
Nigella Sativa ◽  
Fibril Formation ◽  
Order Structure ◽  
Type Ii ◽  
Aggregation Assay ◽  
Insulin Fibrils

The high order structure from proteins which are self-assembled are known as fibrils. They are collectively called as amyloid fibrils, which generally lead to neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, Type II diabetes. Insulin fibril aggregation is identified to be the major cause of neurodegenerative diseases. The effect of Nigella sativa extract is analyzed based on the fibril inhibition process. The formed fibrils is reduced with the concentration increase of Nigella sativa extract. Insulin fibril is found in Type II diabetes patients after repeated insulin injections subcutaneously. Insulin fibrils are formed in organisms or humans irrespective of their places like hips, shoulder, hands and abdomen. These are evident from the anti-aggregation assay. Thioflavin T (ThT) fluroscence and congo red (CR) assay confirms the inhibition of insulin fibril in the presence of Nigella sativa (NS) extract. Further, inhibition of fibril was confirmed by Scanning Electron Microscope (SEM), where no insulin fibrils was detected whose secondary conformational changes are studied using Fourier Transform Infrared spectroscopy (FT-IR). It is confirmed that insulin fibril inhibition depends on the various concentration of Nigella sativa. Based on the results obtained, it is demonstrated that Nigella sativa extract inhibits the fibril formation and it also provides a therapeutic strategy to prevent insulin fibril formation.

scholarly journals Conformational change, aggregation and fibril formation induced by detergent treatments of cellular prion protein

2008 ◽  
Vol 79 (3) ◽  
pp. 669-678 ◽  
Author(s):  
Liang-Wen Xiong ◽  
Lynne D. Raymond ◽  
Stanley F. Hayes ◽  
Gregory J. Raymond ◽  
Byron Caughey
Keyword(s):  
Conformational Change ◽  
Prion Protein ◽  
Fibril Formation ◽  
Cellular Prion Protein

scholarly journals Structural Consequences of Copper Binding to the Prion Protein

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 770 ◽  
Author(s):  
Giulia Salzano ◽  
Gabriele Giachin ◽  
Giuseppe Legname
Keyword(s):  
Prion Protein ◽  
Animal Species ◽  
State Of The Art ◽  
Copper Ions ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Copper Binding ◽  
Spongiform Encephalopathies ◽  
And Function

Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability to bind copper ions through its flexible N-terminal moiety. This review includes an overview of the structure and function of PrPC with a focus on its ability to bind copper ions. The state-of-the-art of the role of copper in both PrPC physiology and in prion pathogenesis is also discussed. Finally, we describe the structural consequences of copper binding to the PrPC structure.

scholarly journals Interaction between Shadoo and PrP Affects the PrP-Folding Pathway

2015 ◽  
Vol 89 (12) ◽  
pp. 6287-6293 ◽  
Author(s):  
Danica Ciric ◽  
Charles-Adrien Richard ◽  
Mohammed Moudjou ◽  
Jérôme Chapuis ◽  
Pierre Sibille ◽  
...  
Keyword(s):  
Prion Protein ◽  
Conformational Changes ◽  
Conversion Rate ◽  
Biochemical Characterization ◽  
Direct Interaction ◽  
Cellular Prion Protein ◽  
Dominant Negative ◽  
Folding Pathway ◽  
Replication Process ◽  
Binding Behavior

ABSTRACTPrion diseases are characterized by conformational changes of a cellular prion protein (PrPC) into a β-sheet-enriched and aggregated conformer (PrPSc). Shadoo (Sho), a member of the prion protein family, is expressed in the central nervous system (CNS) and is highly conserved among vertebrates. On the basis of histoanatomical colocalization and sequence similarities, it is suspected that Sho and PrP may be functionally related. The downregulation of Sho expression during prion pathology and the direct interaction between Sho and PrP, as revealed by two-hybrid analysis, suggest a relationship between Sho and prion replication. Using biochemical and biophysical approaches, we demonstrate that Sho forms a 1:1 complex with full-length PrP with a dissociation constant in the micromolar range, and this interaction consequently modifies the PrP-folding pathway. Using a truncated PrP that mimics the C-terminal C1 fragment, an allosteric binding behavior with a Hill number of 4 was observed, suggesting that at least a tetramerization state occurs. A cell-based prion titration assay performed with different concentrations of Sho revealed an increase in the PrPScconversion rate in the presence of Sho. Collectively, our observations suggest that Sho can affect the prion replication process by (i) acting as a holdase and (ii) interfering with the dominant-negative inhibitor effect of the C1 fragment.IMPORTANCESince the inception of the prion theory, the search for a cofactor involved in the conversion process has been an active field of research. Although the PrP interactome presents a broad landscape, candidates corresponding to specific criteria for cofactors are currently missing. Here, we describe for the first time that Sho can affect PrP structural dynamics and therefore increase the prion conversion rate. A biochemical characterization of Sho-PrP indicates that Sho acts as an ATP-independent holdase.

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