共查询到20条相似文献,搜索用时 155 毫秒
1.
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
2.
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
3.
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
4.
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
5.
Prion diseases are fatal neurodegenerative and infectious disorders of humans and animals, characterized by structural transition
of the host-encoded cellular prion protein (PrPc) into the aberrantly folded pathologic isoform PrPSc. RNA, DNA or peptide aptamers are classes of molecules which can be selected from complex combinatorial libraries for high
affinity and specific binding to prion proteins and which might therefore be useful in diagnosis and therapy of prion diseases.
Nucleic acid aptamers, which can be chemically synthesized, stabilized and immobilized, appear more suitable for diagnostic
purposes, allowing use of PrPSc as selection target. Peptide aptamers facilitate appropriate intracellular expression, targeting and re-routing without losing
their binding properties to PrP, a requirement for potential therapeutic gene transfer experiments in vivo. Elucidation of
structural properties of peptide aptamers might be used as basis for rational drug design, providing another attractive application
of peptide aptamers in the search for effective anti-prion strategies. 相似文献
6.
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
7.
Protein misfolding and disease: the case of prion disorders 总被引:2,自引:0,他引:2
Recent findings strongly support the hypothesis that diverse human disorders, including the most common neurodegenerative
diseases, arise from misfolding and aggregation of an underlying protein. Despite the good evidence for the involvement of
protein misfolding in disease pathogenesis, the mechanism by which protein conformational changes participate in the disease
is still unclear. Among the best-studied diseases of this group are the transmissible spongiform encephalopathies or prion-related
disorders, in which misfolding of the normal prion protein plays a key role in the disease. In this article we review recent
data on the link between prion protein misfolding and the pathogensis of spongiform encephalopathies.
Received 15 July 2002; received after revision 19 August 2002; accepted 23 August 2002
RID="*"
ID="*"Corresponding author. 相似文献
8.
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
9.
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
10.
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
11.
Stoltze L Rezaei H Jung G Grosclaude J Debey P Schild H Rammensee HG 《Cellular and molecular life sciences : CMLS》2003,60(3):629-638
The prion protein (PrP(C)) is essential for susceptibility to transmissible spongiform encephalopathies. A specific conformer of this protein (PrP(Sc)) is, according to the 'protein only' hypothesis, the principal or only component of the infectious agent, designated prion. Transmission of prions between species is often inefficient, resulting in low attack rates and/or prolonged incubation times and is ascribed to a 'species barrier' caused by differences in the amino acid sequence of PrP between recipient and donor. In this report, we demonstrate that these differences in amino acid sequence result in presentation of distinct peptides on major histocompatibility complex class II molecules. These peptides result in activation of specific CD4+ T cells which leads to the induction of an effective immune response against foreign PrP as demonstrated by antibody production. Therefore, CD4+ T cells represent a crucial component of the immune system to distinguish between foreign and self PrP. 相似文献
12.
Faust M Günther J Morgenstern E Montenarh M Götz C 《Cellular and molecular life sciences : CMLS》2002,59(12):2155-2164
The protein kinase CK2 holoenzyme is composed of two regulatory β subunits and two catalytic α or α' subunits. Although experimental
evidence for involvement of the enzyme in the regulation of cell proliferation is accumulating, the exact mechanism of its
action is still unclear. The subcellular localization of the enzyme may be a key to its function. We have recently shown that
the CK2 holoenzyme is tightly associated with the Golgi complex and the endoplasmic reticulum. Centrosomes, which organize
spindle formation during the cell cycle and microtubule cytoskeleton formation and, thereby, the location and orientation
of different organelles in the cell, are in close vicinity to the Golgi complex. Because several kinases and phosphatases
have been described to regulate the functions of the centrosome, we analysed the association of CK2 with these organelles.
Using biochemical cell fractionation and coimmunoprecipitation, we never found the holoenzyme but only the catalytic asubunits
associated with the centrosome. These data were confirmed by immunoelectron microscopy. Thus, the present data point to a
particular role of the catalytic α and α' subunit of protein kinase CK2, which may be different from their roles in the holoenzyme.
Received 2 August 2002; received after revision 2 October 2002; accepted 22 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
13.
ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts 总被引:3,自引:0,他引:3
Fortino V Torricelli C Gardi C Valacchi G Rossi Paccani S Maioli E 《Cellular and molecular life sciences : CMLS》2002,59(12):2165-2171
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
14.
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
15.
Johansson S Gullbo J Lindholm P Ek B Thunberg E Samuelsson G Larsson R Bohlin L Claeson P 《Cellular and molecular life sciences : CMLS》2003,60(1):165-175
Four novel proteins (phoratoxins C–F) have been isolated from the North American mistletoe Phoradendron tomentosum. The amino acid sequences of these phoratoxins were determined unambiguously using a combination of Edman degradation and
trypsin enzymatic digestion, and by electrospray ionization tandem mass spectrometry sequencing. Phoratoxins C, E and F consist
of 46 amino acid residues; and phoratoxin D of 41. All proteins had six cysteines, similar to the earlier described phoratoxins
A and B, which are thionins. The cytotoxicity of each protein was evaluated in a human cell line panel that represented several
cytotoxic drug-resistance mechanisms. For the half-maximal inhibitory concentrations (IC50 values) of the different cell lines in the panel, correlation with those of standard drugs was low. The most potent cytotoxic
phoratoxin C was further tested on primary cultures of human tumor cells from patients. The solid tumor samples from breast
cancer cells were 18 times more sensitive to phoratoxin C than the tested hematological tumor samples.
Received 30 September 2002; received after revision 28 October 2002; accepted 7 November 2002
RID="*"
ID="*"Corresponding author. 相似文献
16.
Prosperi-Meys C de Seny D Llabres G Galleni M Lamotte-Brasseur J 《Cellular and molecular life sciences : CMLS》2002,59(12):2136-2143
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases. X-ray structures of zinc β-lactamases unraveled
the coordination of the metal ions, but their mode of action remains unclear. Recently, enzymes in which one of the zinc ligands
was mutated have been characterized and their catalytic activity against several β-lactam antibiotics measured. A molecular
modeling study of these enzymes was performed here to explain the catalytic activity of the mutants. Coordination around the
zinc ions influences the way the tetrahedral intermediate is bound; any modification influences the first recognition of the
substrate by the enzyme. For all the studied mutants, at least one of the interactions fails, inducing a loss of catalytic
efficiency compared to the wild type. The present studies show that the enzyme cavity is a structure of high plasticity both
structurally and mechanistically and that local modifications may propagate its effects far from the mutated amino
acid.
Received 28 August 2002; received after revision 22 October 2002; accepted 24 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
17.
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
18.
Reuter A Binkle U Stuermer CA Plattner H 《Cellular and molecular life sciences : CMLS》2004,61(16):2092-2099
A new model of caveolin association with lipid body cores has recently been proposed which may be relevant to a number of cellular processes, e.g. lipid body generation. Here we show that PrPc and reggie-1 and reggie-2 also occur in the cores of Nile Red/Bodipy-stained (neutral lipid-containing) vesicular structures and, in immunoblots, in the lipid-enriched fraction after density gradient centrifugation. These lipid-rich vesicles increase in number following cell feeding with oleic acid, differ from early endosome antigen 1- and Lamp-2-positive endosomes/lysosomes, exhibit an opaque content and lack surrounding actin staining. Our results suggest that the content of these vesicles, together with reggie-1 and -2 and PrPc, is expelled.Received 3 May 2004; received after revision 14 June 2004; accepted 23 June 2004 相似文献
19.
Justo R Alcolea MP Colom B Riera AN Gianotti M García-Palmer FJ 《Cellular and molecular life sciences : CMLS》2002,59(12):2199-2209
To establish the role of mitochondrial subpopulations in the mitochondrial maturation process, we studied morphological and
functional changes in the mitochondria of different mammalian conceptus tissues during the organogenic and the placentation
processes. Mitochondrial subpopulations of three different conceptus tissues, embryo and visceral yolk sac placenta on gestational
days 11, 12 and 13 and placenta on days 12 and 13, were examined morphologically by transmission electron microscopy. Cytochrome
oxidase activity and protein levels were also measured in each mitochondrial subpopulation. The results indicate two different
mitochondrial subpopulation profiles: a homogeneous one, which corresponds to immature mitochondria, and a heterogeneous one,
which represents the mature mitochondria. The three tissues studied show different morphologic and metabolic patterns of mitochondrial
maturation during the placentation process, rendering them suitable as experimental models to establish the p
ossible relationship between mitochondrial maturation and the mitochondrial subpopulations.
Received 5 August 2002; received after revision 23 September 2002; accepted 8 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
20.
Guthmann F Maehl P Preiss J Kolleck I Rüstow B 《Cellular and molecular life sciences : CMLS》2002,59(11):1999-2003
Glycoprotein IV (FAT/CD36) has been shown to be phosphorylated by a cAMP-dependent, platelet membrane-bound ectokinase. In
this study, we demonstrate that ectophosphorylation of FAT/CD36 regulates initial palmitate uptake. This is the first time
that short-term regulation of the activity of a long-chain fatty acid carrier could be shown. Phosphorylation of FAT/CD36
was paralleled by a significant decrease in initial palmitate uptake by morphologically and functionally intact platelets.
Maximum inhibition of palmitate uptake was achieved at 0.5 nM extracellular ATP, being significantly decreased to 72% compared
to the control. Inhibition of palmitate uptake was abolished by co-incubation with the specific protein kinase A inhibitor
peptide PKI or with β,γ-methylene-ATP, and was reversible upon addition of alkaline phosphatase. An extracellular ATP concentration
above 5 μM completely prevented the ectophosphorylation-mediated inhibition of palmitate uptake. We conclude that FAT/CD36-mediated
palmitate uptake by human platelets is short-term regulated via cAMP-dependent ectophosphorylation of FAT/CD36.
Received 18 July 2002; received after revision 29 August 2002; accepted 19 September 2002
RID="*"
ID="*"Corresponding author. 相似文献