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1.
Mornon JP Prat K Dupuis F Boisset N Callebaut I 《Cellular and molecular life sciences : CMLS》2002,59(12):2144-2154
Prion diseases are neurodegenerative disorders associated with a conformational conversion of the prion PrP protein, in which
the β-strand content increases and that of the α helix decreases. However, the structure of the pathogenous form PrPSc, occurring after conformational conversion of the normal cellular form PrPC, is not yet known. From sequence analysis, we have previously proposed that helix H2 of the prion PrPC structure might be a key region for this structural conversion. More recently, we identified the TATA box-binding protein
fold as a putative scaffold that may locally satisfy the predicted secondary-structure organisation of PrPSc. In the present analysis, we detail the schematic construction of PrPSc monomeric and dimeric models, based on this hypothesis. These models are globally compatible with available data and therefore
may provide further insights into the structurally and functionally elusive PrP protein.
Some comments are also devoted to a comparison of the yeast Ure2p prion and animal prions.
Received 29 July 2002; received after revision 24 October 2002; accepted 24 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
2.
Sabine Gilch Christian Bach Gloria Lutzny Ina Vorberg Hermann M. Schätzl 《Cellular and molecular life sciences : CMLS》2009,66(24):3979-3991
The infectious agent in prion diseases consists of an aberrantly folded isoform of the cellular prion protein (PrPc), termed PrPSc, which accumulates in brains of affected individuals. Studies on prion-infected cultured cells indicate that cellular cholesterol
homeostasis influences PrPSc propagation. Here, we demonstrate that the cellular PrPSc content decreases upon accumulation of cholesterol in late endosomes, as induced by NPC-1 knock-down or treatment with U18666A.
PrPc trafficking, lipid raft association, and membrane turnover are not significantly altered by such treatments. Cellular PrPSc formation is not impaired, suggesting that PrPSc degradation is increased by intracellular cholesterol accumulation. Interestingly, PrPSc propagation in U18666A-treated cells was partially restored by overexpression of rab 9, which causes redistribution of cholesterol
and possibly of PrPSc to the trans-Golgi network. Surprisingly, rab 9 overexpression itself reduced cellular PrPSc content, indicating that PrPSc production is highly sensitive to alterations in dynamics of vesicle trafficking. 相似文献
3.
Didier Vilette Josquin Courte Jean Michel Peyrin Laurent Coudert Laurent Schaeffer Olivier Andréoletti Pascal Leblanc 《Cellular and molecular life sciences : CMLS》2018,75(14):2557-2574
Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrPSc). These abnormal aggregated PrPSc species multiply in infected cells by recruiting and converting the host PrPC protein into new PrPSc. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrPSc-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrPSc in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative diseases. 相似文献
4.
Yuan J Dong Z Guo JP McGeehan J Xiao X Wang J Cali I McGeer PL Cashman NR Bessen R Surewicz WK Kneale G Petersen RB Gambetti P Zou WQ 《Cellular and molecular life sciences : CMLS》2008,65(4):631-643
Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated
PrP27 – 30 detectable by the 3F4 antibody against human PrP109 – 112. We recently identified a new PK-resistant PrP species,
designated PrP*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 – 108 but
not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility
of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic
mutant PrP accumulate not only PrP*20 but also a small amount of 3F4-detected PK-resistant PrP27 – 30. Remarkably, during the course of human prion disease, a
transition from an increase in 1E4-detected PrP*20 to the occurrence of the 3F4-detected PrP27 – 30 was observed. Our study suggests that an increase in the level of PrP*20 characterizes the early stages of prion diseases.
Received 17 October 2007; received after revision 5 December 2007; accepted 14 December 2007 相似文献
5.
Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases associated with progressive oligo- and multimerization
of the prion protein (PrPC), its conformational conversion, aggregation and precipitation. We recently proposed that PrPC serves as a cell surface scaffold protein for a variety of signaling modules, the effects of which translate into wide-range
functional consequences. Here we review evidence for allosteric functions of PrPC, which constitute a common property of scaffold proteins. The available data suggest that allosteric effects among PrPC and its partners are involved in the assembly of multi-component signaling modules at the cell surface, impose upon both
physiological and pathological conformational responses of PrPC, and that allosteric dysfunction of PrPC has the potential to entail progressive signal corruption. These properties may be germane both to physiological roles of
PrPC, as well as to the pathogenesis of the TSEs and other degenerative/non-communicable diseases. 相似文献
6.
Silvia Lisa Massimiliano Meli Gema Cabello Ruth Gabizon Giorgio Colombo María Gasset 《Cellular and molecular life sciences : CMLS》2010,67(16):2825-2838
The conversion of the cellular prion protein (PrPC) into its disease-associated form (PrPSc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches
have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility
required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated
M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation
is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing
a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity,
reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206
and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes. 相似文献
7.
Glaucia N. M. Hajj Camila P. Arantes Marcos Vinicios Salles Dias Martín Roffé Bruno Costa-Silva Marilene H. Lopes Isabel Porto-Carreiro Tatiana Rabachini Flávia R. Lima Flávio H. Beraldo Marco M. A. Prado Rafael Linden Vilma R. Martins 《Cellular and molecular life sciences : CMLS》2013,70(17):3211-3227
The co-chaperone stress-inducible protein 1 (STI1) is released by astrocytes, and has important neurotrophic properties upon binding to prion protein (PrPC). However, STI1 lacks a signal peptide and pharmacological approaches pointed that it does not follow a classical secretion mechanism. Ultracentrifugation, size exclusion chromatography, electron microscopy, vesicle labeling, and particle tracking analysis were used to identify three major types of extracellular vesicles (EVs) released from astrocytes with sizes ranging from 20–50, 100–200, and 300–400 nm. These EVs carry STI1 and present many exosomal markers, even though only a subpopulation had the typical exosomal morphology. The only protein, from those evaluated here, present exclusively in vesicles that have exosomal morphology was PrPC. STI1 partially co-localized with Rab5 and Rab7 in endosomal compartments, and a dominant-negative for vacuolar protein sorting 4A (VPS4A), required for formation of multivesicular bodies (MVBs), impaired EV and STI1 release. Flow cytometry and PK digestion demonstrated that STI1 localized to the outer leaflet of EVs, and its association with EVs greatly increased STI1 activity upon PrPC-dependent neuronal signaling. These results indicate that astrocytes secrete a diverse population of EVs derived from MVBs that contain STI1 and suggest that the interaction between EVs and neuronal surface components enhances STI1–PrPC signaling. 相似文献
8.
Peptide aptamers have emerged as powerful new tools for molecular medicine. They can specifically bind to and functionally
inactivate a given target molecule under intracellular conditions. Typically, peptide aptamers are generated by screening
a randomized peptide expression library, displayed from the Escherichia coli thioredoxin A (TrxA) protein. Here, we transferred peptide moieties from defined TrxA-based peptide aptamers to alternative
scaffold proteins, such as the green fluorescent protein and staphylococcal nuclease. Yeast and mammalian two-hybrid assays
as well as in vitro binding analyses show that the TrxA scaffold can be a major determinant for the binding of peptide aptamers.
In addition, we demonstrate that TrxA can correctly display peptide sequences that correspond to the binding domains of natural
interaction partners. Therefore, sequence analyses of TrxA-based peptide aptamers, isolated by two-hybrid screening from randomized
expression libraries, should also be useful to find cellular binding partners for a given target protein, by homology.
Received 1 August 2002; received after revision 17 September 2002; accepted 19 September 2002
RID="*"
ID="*"Corresponding author. 相似文献
9.
Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts 总被引:3,自引:0,他引:3
Hugel B Martínez MC Kunzelmann C Blättler T Aguzzi A Freyssinet JM 《Cellular and molecular life sciences : CMLS》2004,61(23):2998-3007
Because expressed at a significant level at the membrane of human T cells, we made the hypothesis that the cellular prion protein (PrPc) could behave as a receptor, and be responsible for signal transduction. PrPc engagement by specific antibodies was observed to induce an increase in cytosolic calcium concentration and led to enhanced activity of Src protein tyrosine kinases. Antibodies to CD4 and CD59 did not influence calcium fluxes or signaling. The effect was maximal after the formation of a network involving avidin and biotinylated antibody to PrPc and was inhibited after raft disruption. PrPc localization was not restricted to rafts in resting cells but engagement was a prerequisite for signaling induction, with concomitant PrPc recruitment into rafts. These results suggest a role for PrPc in signaling pathways, and show that lateral redistribution of the protein into rafts is important for subsequent signal transduction.Received 22 July 2004; received after revision 10 September 2004; accepted 7 October 2004 相似文献
10.
Catherine Aude-Garcia Christian Villiers Serge M. Candéias Catherine Garrel Caroline Bertrand Véronique Collin Patrice N. Marche Evelyne Jouvin-Marche 《Cellular and molecular life sciences : CMLS》2011,68(4):687-696
The cellular prion glycoprotein (PrPC) is ubiquitously expressed but its physiologic functions remain enigmatic, particularly in the immune system. Here, we demonstrate
in vitro and in vivo that PrPC is involved in T lymphocytes response to oxidative stress. By monitoring the intracellular level of reduced glutathione,
we show that PrP−/− thymocytes display a higher susceptibility to H2O2 exposure than PrP+/+ cells. Furthermore, we find that in mice fed with a restricted diet, a regimen known to increase the intracellular level
of ROS, PrP−/− thymocytes are more sensitive to oxidative stress. PrPC function appears to be specific for oxidative stress, since no significant differences are observed between PrP−/− and PrP+/+ mice exposed to other kinds of stress. We also show a marked evolution of the redox status of T cells throughout differentiation
in the thymus. Taken together, our results clearly ascribe to PrPC a protective function in thymocytes against oxidative stress. 相似文献
11.
Q.-Q. Li X.-X. Cao J.-D. Xu Q. Chen W.-J. Wang F. Tang Z.-Q. Chen X.-P. Liu Z.-D. Xu 《Cellular and molecular life sciences : CMLS》2009,66(3):504-515
We previously reported that treatment with P-glycoprotein (P-gp) substrates promotes in vitro invasion in multidrug-resistant (MDR) breast cancer cells. This effect is initiated by the P-gp pump function and mediated
by interaction of P-gp with some unknown component(s). However, the underlying mechanism(s) remains poorly understood. Here
we confirm a novel physical interaction between P-gp and cellular prion protein (PrPc). Blocking P-gp activity or depletion of PrPc inhibited paclitaxel (P-gp substrate)- induced invasion. Paclitaxel further facilitated the formation of P-gp/PrPc clusters residing in caveolar domains and promoted the association of P-gp with caveolin-1. Both caveolin-1 and the integrity
of caveolae were required for the drug-induced invasion. In addition, the P-gp/PrPc complex also played an important role in anti-apoptotic activity of MCF7/Adr cells.These data provide new insights into the
mode by which MDR breast cancers evade cytotoxic attacks from P-gp substrates and also suggest a role for P-gp/ PrPc interaction in this process.
Received 4 September 2008; received after revision 16 November 2008; accepted 18 November 2008 相似文献
12.
Prion protein, a misfolded isoform of which is the essential component of the agent of prion diseases, still remains an enigmatic
protein whose physiological functions are at best hypothetical. To gain a better insight into its putative role, many studies
were undertaken to look for molecules that bind prion protein, and have notably identified divalent metal ions, several proteins,
and nucleic acids. At first sight, the diversity of prion protein’s ligands seems of little help to infer a plausible function.
However, the intrinsically disordered property of its N-terminal tail and the potential of the protein to adopt a transmembrane
topology, can both be taken into account to predict its different states during its cellular cycle and its possible functions,
of which the most promising correspond to a general scavenger, a sensor or adaptor in a signaling cascade, and an RNA chaperone.
Received 16 August 2006; received after revision 7 November 2006; accepted 13 December 2006 相似文献
13.
A. Aguzzi T. Blättler M. A. Klein A. J. Räber I. Hegyi R. Frigg S. Brandner C. Weissmann 《Cellular and molecular life sciences : CMLS》1997,53(6):485-495
The physical nature of the agent that causes transmissible spongiform encephalopathies (the 'prion'), is the subject of passionate
controversy. Investigation of it has benefited tremendously from the use of transgenic and knockout technologies. However,
prion diseases present several other enigmas, including the mechanism of brain damage and how the affinity of the agent for
the central nervous system is controlled. Here we show that such questions can be effectively addressed in transgenic and
knockout systems, and that pathogenesis may be clarified even before we can be certain about the nature of the infectious
agent. Availability of mice overexpressing the Prnp gene (which encodes the normal prion protein) and Prnp knockout mice allows for selective reconstitution experiments aimed at expressing PrP in specific portions of the brain or
in selected populations of hemato- and lymphopoietic origin. We summarize how such studies can offer insights into how prions
administered to peripheral sites can gain access to central nervous tissue, and into the molecular requirements for spongiform
brain damage. 相似文献
14.
Beatriz Domingo María Gasset Mario Durán-Prado Justo P. Castaño Antonio Serrano Thierry Fischer Juan Llopis 《Cellular and molecular life sciences : CMLS》2010,67(19):3345-3354
Membrane protein function is determined by the relative organization of the protein domains with respect to the membrane.
We have experimentally verified the topology of a protein with diverse orientations arising from a single primary sequence
(the cellular prion protein, PrPC), a novel somatostatin truncated receptor, and the Golgi-associated protein GPBP91. Tagging with fluorescent proteins (FP) allows location of their expression at the plasma membrane or at endomembranes, but
does not inform about their orientation. Exploiting the pH dependency of some FPs, we developed a pH exchange assay in which
extracellularly exposed FPs are quenched by application of low pH buffer. We constructed standards to demonstrate and calibrate
the assay, and the method was adapted for acidic organelle membrane proteins. This method can serve as a proof of concept,
experimentally confirming and/or discriminating in living cells among theoretical topology predictions, providing the proportion
of inside/outside orientation for proteins with multiple forms. 相似文献
15.
Iva Hafner-Bratkovi? Mojca Ben?ina Katherine A. Fitzgerald Douglas Golenbock Roman Jerala 《Cellular and molecular life sciences : CMLS》2012,69(24):4215-4228
Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K+, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease. 相似文献
16.
GPR39 is a vertebrate G protein-coupled receptor related to the ghrelin/neurotensin receptor subfamily. The receptor is expressed
in a range of tissues including the pancreas, gut/gastrointestinal tract, liver, kidney and in some regions of the brain.
GPR39 was initially thought to be the cognitive receptor for the peptide hormone, obestatin. However, subsequent in vitro
studies have failed to demonstrate binding of this peptide to the receptor. Zn2+ has been shown to be a potent stimulator of GPR39 activity via the Gαq, Gα12/13 and Gαs pathways. The potency and specificity of Zn2+ in activating GPR39 suggest it to be a physiologically important agonist. GPR39 is now emerging as an important transducer
of autocrine and paracrine Zn2+ signals, impacting upon cellular processes such as insulin secretion, gastric emptying, neurotransmission and epithelial
repair. This review focuses on the molecular, structural and biological properties of GPR39 and its various physiological
functions. 相似文献
17.
Interleukin-8 is a Cyclosporin A binding protein 总被引:2,自引:0,他引:2
H. Bang K. Brune C. Nager U. Feige 《Cellular and molecular life sciences : CMLS》1993,49(6-7):533-538
Inflammatory immune reactions occur during transplant rejections and autoimmune diseases. Such reactions are mediated by cytokines, including interleukin-8 (IL-8). Cyclosporin A (CsA) exerts immunosuppressive activities1,2 by binding to immunoregulatory proteins termed cyclophilins3. The anti-inflammatory effects of CsA are still not fully understood. Searching for novel neutrophil-activating proteins, we observed that an antiserum against human recombinant Interleukin-8 (IL-8) cross-reacted with cyclophilins in Western blots. Furthermore, native IL-8 was found to specifically bind CsA, whereas biologically inactive analogs of CsA were not bound by IL-8. Putative binding sites for CsA on IL-8 could be identified on the basis of structural similarities between IL-8 and cyclophilin. However, IL-8 lacks peptidyl-prolyl-isomerase (PPlase) enzyme activity, which is regarded as a characteristic of cyclophilins4,5,6. We conclude that the specific binding of CsA to IL-8 may explain some of the anti-inflammatory effects of CsA. IL-8 may be a novel member of the cyclophilins lacking PPlase activity. 相似文献
18.
We need to understand the underlying factors that promote or reverse the amyloid-type structure of the prion protein (PrP). In an earlier study, we showed that mutations within the first strand can extend the short sheet in the normal protein into a larger sheet at neutral pH. To determine the impact of the point mutation P102L and the deletion of either the first or the second strand on PrP, we performed further long molecular explicit water dynamics simulations. The trajectories show that all mutations do not exert a uniform effect on the dynamics of the N-terminal tail. The results of the deletion of the two strands confirm the idea that partially unfolded conformations are involved in the structural transition. In the deletion variants, the helices H2 and H3 are disordered, while helix H1 is either fully stable or partially disordered. This finding, consistent with recent spectroscopic analyses on peptides spanning helix H1 and flanking sequences, demonstrates that unfolding of the full domain containing helix H1 is not an early step in PrP interconversion. This result also raises questions regarding a current view of PrPSc structure that transforms helix H1 into a sheet conformation.Received 16 December 2003; received after revision 16 January 2004; accepted 21 January 2004 相似文献
19.
From Creutzfeldt-Jakob disease (CJD) to variant CJD through Gerstmann-Str?ussler-Scheinker syndrome, kuru and fatal familial insomnia, the journey leading to current understanding of the basic aspects of human prion diseases has been full of unexpected, but often dramatic and always fascinating twists. Recent progress in modeling prion diseases and characterization of the various prion protein forms reveal that such a wide spectrum of the diseases is associated with the chameleon-like conformational features of prions. 相似文献
20.
Mornon JP Prat K Dupuis F Callebaut I 《Cellular and molecular life sciences : CMLS》2002,59(8):1366-1376
Animal prion proteins (PrPs) form at the sequence level a very homogenous and 'closed' family. Therefore, few of their structural and functional features can be gleaned from sequence comparison as is now possible on a wide scale for other protein families. To detect putatively related proteins (at the structural and/or functional level), we used a battery of sequence analysis tools. This analysis resulted in (i) the identification of a putative 'prion-like' domain within the envelope of foamy retroviruses, (ii) the detection of putative similarities between prions and an interferon-inducible membrane protein, and (iii) the proposal that of the TATA-box-binding protein is a structural scaffold, which might allow understanding of a key event leading to the structural conversion from PrP(C) (normal cellular prion structure) towards PrP(Sc) (pathogenic structure). 相似文献