共查询到20条相似文献,搜索用时 93 毫秒
1.
Bandholtz L Guo Y Palmberg C Mattsson K Ohlsson B High A Shabanowitz J Hunt DF Jörnvall H Wigzell H Agerberth B Gudmundsson GH 《Cellular and molecular life sciences : CMLS》2003,60(2):422-429
CpG motifs originating from bacterial DNA (CpG DNA) can act as danger signals for the mammalian immune system. These CpG
DNA motifs like many other pathogen-associated molecular patterns are believed to be recognized by a member of the toll-like
receptor family, TLR-9. Here we show results suggesting that heat shock protein 90 (hsp90) is also implicated in the recognition
of CpG DNA. Hsp90 was characterized as a binder to oligodeoxynucleotides (ODNs) containing CpG motifs (CpG ODNs) after several
purification steps from crude protein extracts of peripheral blood mononuclear cells. This finding was further supported by
direct binding of CpG ODNs to commercially available human hsp90. Additionally, immunohistochemistry studies showed redistribution
of hsp90 upon CpG ODN uptake. Thus, we propose that hsp90 can act as a ligand transfer molecule and/or play a central role
in the signaling cascade induced by CpG DNA.
Received 18 December 2002; accepted 6 January 2002
RID="*"
ID="*"Corresponding author. B. Agerberth and G. H. Gudmundsson contributed equally to this work. 相似文献
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Mariann Kremlitzka Bernadett Mácsik-Valent Anna Erdei 《Cellular and molecular life sciences : CMLS》2015,72(11):2223-2236
B cells are efficiently activated by CpG oligodeoxynucleotides (ODNs) to produce pro-inflammatory cytokines and antibody (Ab). Here, we describe a so far unidentified, spleen tyrosine kinase (Syk)-dependent pathway, which is indispensable for CpG-induced human B cell activation. We show that triggering of B cells by CpG results in Syk and src kinase phosphorylation, proliferation, as well as cytokine and Ab production independent of the BCR. Notably, all these functions are abrogated when Syk is inhibited. We demonstrate that CpG-induced Syk activation originates from the cell surface in a TLR9-dependent manner. While inhibition of Syk does not influence the uptake of CpG ODNs, activation of the kinase is a prerequisite for the delivery of CpG into TLR9-containing endolysosomes and for the CpG-induced up-regulation of TLR9 expression. Our results reveal an alternative, Syk-dependent pathway of CpG-induced B cell stimulation, which is initiated at the plasma membrane and seems to be an upstream requirement for endosomal TLR9-driven B cell proliferation and differentiation. 相似文献
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Development and application of therapeutic oligonucleotides rely on proper analysis of binding and uptake. We have used several
model oligodeoxynucleotides (ODNs) to analyze binding/uptake by rat and human leukocytes. Here we describe: (1) differences
between in vivo and in vitro uptake of ODNs to rat leukocytes, (2) differences after injection of lipopolysaccharide (LPS), (3) large in vitro differences between primary mononuclear cells in PBS, plasma and blood, and (4) differences of ODN uptake between rat and
human leukocytes. Our data show that ODN uptake by primary blood cells was different in PBS, plasma and blood. In addition,
LPS treatment increased ODN uptake by leukocytes in blood, indicating that pathological conditions may influence ODN uptake.
Furthermore, ODN uptake in rat and human blood is also different, suggesting that preclinical ODN uptake data from rat blood
cannot easily be extrapolated to the human condition.
Received 17 December 2007; received after revision 16 January 2008; accepted 5 February 2008 相似文献
5.
Wesch D Peters C Oberg HH Pietschmann K Kabelitz D 《Cellular and molecular life sciences : CMLS》2011,68(14):2357-2370
Toll-like receptors (TLR) are pattern-recognition receptors that recognize a broad variety of structurally conserved molecules
derived from microbes. The recognition of TLR ligands functions as a primary sensor of the innate immune system, leading to
subsequent indirect activation of the adaptive immunity as well as none-immune cells. However, TLR are also expressed by several
T cell subsets, and the respective ligands can directly modulate their effector functions. The present review summarizes the
recent findings of γδ T cell modulation by TLR ligands. TLR1/2/6, 3, and 5 ligands can act directly in combination with T
cell receptor (TCR) stimulation to enhance cytokine/chemokine production of freshly isolated human γδ T cells. In contrast
to human γδ T cells, murine and bovine γδ T cells can directly respond to TLR2 ligands with increased proliferation and cytokine
production in a TCR-independent manner. Indirect stimulatory effects on IFN-γ production of human and murine γδ T cells via
TLR-ligand activated dendritic cells have been described for TLR2, 3, 4, 7, and 9 ligands. In addition, TLR3 and 7 ligands
indirectly increase tumor cell lysis by human γδ T cells, whereas ligation of TLR8 abolishes the suppressive activity of human
tumor-infiltrating Vδ1 γδ T cells on αβ T cells and dendritic cells. Taken together, these data suggest that TLR-mediated
signals received by γδ T cells enhance the initiation of adaptive immune responses during bacterial and viral infection directly
or indirectly. Moreover, TLR ligands enhance cytotoxic tumor responses of γδ T cells and regulate the suppressive capacity
of γδ T cells. 相似文献
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Viviani VR 《Cellular and molecular life sciences : CMLS》2002,59(11):1833-1850
Luciferases are the enzymes that catalyze the reactions that produce light in bioluminescence. Whereas the oxidative mechanism
which leads to light emission is similar for most luciferases, these enzymes and their substrates are evolutionarily unrelated.
Among all bioluminescent groups, insects constitute one of the most diverse in terms of biochemistry. In the fungus-gnats
(Mycetophilidae: Diptera), for example, bioluminescence is generated by two biochemically distinct systems. Despite the diversity,
investigations on insect luciferases and biochemistry have been conducted mostly with fireflies. The luciferases from the
related phengodid beetles, which can produce green to red bioluminescence using the same chemistry as firefly luciferases,
have been recently investigated. Beetle luciferases originated from ancestral acyl-CoA ligases. Present data suggest that
conserved motifs among this class of ligases are involved in substrate adenylation. The three-dimensional structure of firefly
luciferase was recently solved and mutagenesis studies have been performed identifying putative residues involved in luciferin
binding and bioluminescence color determination in several beetle luciferases. The knowledge gained through these studies
is helping in the development of useful reporter gene tools for biotechnological and biomedical purposes.
Received 4 March 2002; received after revision 13 May 2002; accepted 21 May 2002 相似文献
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Phosphorylation-dependent prolyl isomerization: a novel signaling regulatory mechanism 总被引:7,自引:0,他引:7
Protein phosphorylation on serine or threonine residues preceding proline (Ser/Thr-Pro) plays an essential role for regulating various cellular processes, including cell cycle progression. Although phosphorylation has been proposed to regulate the function of a protein by inducing conformational changes, much less is known about what phosphate additions actually do and how the functions of phosphoproteins are coordinated. Proline is important for determining protein structure because it exists in cis or trans conformation and can put kinks into a polypeptide chain. We have shown that phosphorylation on Ser/Thr-Pro motifs reduces the cis/trans isomerization rate of Ser/Thr-Pro bonds. At the same time, proteins containing phosphorylated Ser/Thr-Pro motifs are substrates for the prolyl isomerase Pin1. The WW domain of Pin1 acts as a phosphoserine/threonine-binding module binding a defined subset of mitosis-specific phosphoproteins, such as Cdc25 and tau. These interactions target the enzymatic activity of Pin1 close to its substrates. In contrast to other prolyl isomerases (peptidyl-prolyl isomerases, PPlases), Pin1 has an extremely high degree of substrate specificity, specifically isomerizing phosphorylated Ser/Thr-Pro bonds. Therefore, Pin1 binds and regulates the function of a defined subset of phosphoproteins. Furthermore, inhibiting Pin1 function is lethal for dividing cells. Interestingly, Pin1, which can restore the biological function of phosphorylated tau, is sequestered in the neurofibrillary tangles in Alzheimer's brains. Thus, we have proposed a novel signaling regulatory mechanism, where protein phosphorylation creates binding sites for Pin1, which can then latch on to and isomerize the phosphorylated Ser/Thr-Pro peptide bond. In turn, this may change the shape of the protein, regulating its activity, dephosphorylation, degradation or location in the cell. This new post-phosphorylation regulatory mechanism appears to play an important role in normal cell function, such as mitotic progression, and in the pathogenesis of some human pathologies, such as Alzheimer's disease. 相似文献
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Dimeric dihydrodiol dehydrogenase (DD) catalyzes the NADP(+)-dependent oxidation of trans-dihydrodiols of aromatic hydrocarbons to their corresponding catechols. The tertiary structure of dimeric DD consists of a classical dinucleotide binding domain comprising two betaalphabetaalphabeta motifs at the N-terminus, and an eight-stranded, predominantly anti-parallel beta-sheet, forming the C-terminal domain The aim of this review is to summarize the biochemical and structural properties of dimeric DD, compare it to enzymes that are structurally similar, and provide an insight into its catalytic mechanism and membership amongst a unique family of monomeric/oligomeric proteins that most likely share a common ancestry. 相似文献
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Dreschers S Dumitru CA Adams C Gulbins E 《Cellular and molecular life sciences : CMLS》2007,64(2):181-191
Rhinoviruses, which cause common cold, belong to the Picornaviridae family, small non-enveloped viruses (diameter 15-30 nm) containing a single-stranded RNA genome (about 7 kb). Over 100 different rhinoviral serotypes have been identified thus far, establishing rhinoviruses as the most diverse group of Picornaviridae. Based on receptor binding properties, rhinoviruses are divided into two classes: the major group binding to intracellular adhesion molecule-1 and the minor group binding to the very low density lipoprotein receptors. Interactions between virus and the receptor molecules cause a conformational change in the capsid, which is a prerequisite for viral uptake. Rhinoviruses trigger a chemokine response upon infection that may lead to exacerbation of the symptoms of common cold, i.e. asthma and inflammation. The following review aims to summarize the knowledge about rhinoviral infections and discusses therapeutical approaches against this almost perfectly adapted pathogen. 相似文献
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Raskin C Gérard C Donfut S Giannotta E Van Driessche G Van Beeumen J Dusart J 《Cellular and molecular life sciences : CMLS》2003,60(7):1460-1469
Streptomyces cacaoi -lactamase genes are controlled
by two regulators named blaA and
blaB. Whereas BlaA has been identified as a LysR-type activator,
the function of BlaB is still unknown. Its primary structure is similar to that of the serine
penicillin-recognizing enzymes (PREs). Indeed, the SXXK and KTG motifs are perfectly conserved in
BlaB, whereas the common SXN element found in PREs is replaced by a SDG motif. Site-directed
mutations were introduced in these motifs and they all disturb -lactamase regulation. A
water-soluble form of BlaB was also overexpressed in the
Streptomyces lividans TK24 cytoplasm and purified.
To elucidate the activity of BlaB, several compounds recognized by PREs were tested. BlaB could be
acylated by some of them, and it can therefore be considered as a penicillin-binding protein. BlaB
is devoid of -lactamase, D-aminopeptidase, DD-carboxypeptidase or thiolesterase activity.Received 13 January 2003; received after revision 9 April 2003; accepted 11 April 2003 相似文献
17.
Ping Song Tharmarajan Ramprasath Huan Wang Ming-Hui Zou 《Cellular and molecular life sciences : CMLS》2017,74(16):2899-2916
Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine amino-transferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP enzyme inhibitors against CVD is briefly discussed. 相似文献
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Protein C inhibitor (PCI) is a widely distributed, multifunctional member of the serpin family of protease inhibitors, and
has been implicated in several physiological processes and disease states. Its inhibitory activity and specificity are regulated
by binding to cofactors such as heparin, thrombomodulin and phospholipids, and it also appears to have non-inhibitory functions
related to hormone and lipid binding. Just how the highly conserved serpin architecture can support the multiple diverse functions
of PCI is a riddle best addressed by protein crystallography. Over the last few years we have solved the structure of PCI
in its native, cleaved and protein-complexed states. They reveal a conserved serpin fold and general mechanism of protease
inhibition, but with some unique features relating to inhibitory specificity/promiscuity, cofactor binding and hydrophobic
ligand transport.
Received 1 July 2008; received after revision 16 August 2008; accepted 22 August 2008 相似文献
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Jean-Baptiste G Yang Z Greenwood MT 《Cellular and molecular life sciences : CMLS》2006,63(17):1969-1985
Regulator of G-Protein Signaling (RGS) refers to a conserved 120–125 amino acid motif that was first identified by its ability
to negatively regulate G-Protein-Coupled Receptor (GPCR) signalling. Mechanistically, RGSs were found to regulate GPCR responses
by binding to and stimulating the GTPase activity of the receptor-activated GTP-bound G α subunits. There are now over 25
mammalian RGSs containing proteins that are reported to carry out a variety of functions, many of which are unrelated to GPCR
signalling. RGS proteins range in size from small proteins that contain little more than an RGS box to very large proteins
that contain a variety of domains. The selectivity of function of the RGS proteins is attributable to the divergence of the
RGS sequences as well as the presence of a variety of functional motifs, which allow them to interact with other proteins.
Here we focus on the RGSs that are involved in modulating GPCR signalling by reviewing the diversity of the mechanisms involved
in regulating these RGSs.
Received 9 February 2006; received after revision 4 May 2006; accepted 22 May 2006 相似文献