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Das erstmals Ende 2002 im Süden Chinas aufgetretene schwere akute respiratorische Syndrom (SARS) führte bis zum August 2003 zu insgesamt über 8000 Erkrankungen und über 700 Todesfällen. Eine von der Weltgesundheitsorganisation (WHO) ins Leben gerufene Kooperation verschiedener Laboratorien weltweit ermöglichte innerhalb von nur vier Wochen die Identifizierung des kausalen Agens, eines bislang unbekannten Coronavirus (vorläufig bezeichnet als SARS-assoziiertes Coronavirus oder SARS-CoV), welches die Koch’schen Postulate erfüllt. Der Erreger lässt sich (unter Hochsicherheitsbedingungen) gut in Zellkulturen vermehren, was weitere Studien zur Stabilität sowie die Entwicklung von antiviral wirksamen Substanzen und Impfstoffen erleichtert.
Obwohl schon rasch diagnostische Labortests, insbesondere zum Nachweis der viralen Nukleinsäure und virusspezifischer Antikörper, zur Verfügung standen, basiert die Falldefinition von SARS weiterhin auf klinisch-epidemiologischen Kriterien. In Hinblick auf die Gefahr eines (saisonalen) Wiederauftretens der Infektion müssen die verfügbaren Labormethoden dringend überprüft und weiter verbessert werden.
SARS ist ein gutes Beispiel dafür, wie schnell sich eine Infektionskrankheit über den internationalen Reiseverkehr ausbreiten kann, aber auch dafür, wie wichtig in einem solchen Falle eine gut koordinierte internationale Kooperation ist; durch Einsatz neuester, aber auch bewährter konventioneller Labormethoden und ständigen Austausch aktueller (Zwischen-)Ergebnisse sowie von Patientenproben und Reagenzien führte eine bisher einmalige Zusammenarbeit schnell zu einem Durchbruch. Dies lässt auf ähnliche Fortschritte beim Kampf gegen weitere neuartige Infektionserreger hoffen.
Women with thrombophilic defects have been shown to be at increased risk, not only of pregnancy associated thromboembolism but also of other vascular complications of pregnancy, including preeclampsia and fetal loss. First trimester fetal loss is associated with factor V Leiden mutation, activated protein C resistance without factor V Leiden mutation and prothrombin G20210A mutation. Late nonrecurrent fetal loss is associated with factor V Leiden mutation, prothrombin mutation and protein S deficiency. Concerning acquired thrombophilia, recurrent fetal loss is a well-documented finding in patients with antiphospholipid antibodies. Associations between thrombophilia polymorphisms and an increased risk of intrauterine growth restriction have been discussed in small series of cases but could not be confirmed in large scale studies. Frequencies for anticardiolipin antibodies or lupus anticoagulants and antinuclear antibodies were significantly higher in women with infants small for gestational age compared to controls. Concerning preeclampsia, gestational hypertension and thrombophilia, a number of studies have examined these relationships with conflicting results. For factor V Leiden, MTHFR C677T and prothrombin mutation, no association with preeclampsia was observed, when severe cases were excluded. If studies were restricted to those of severe preeclampsia, an association with the factor V Leiden mutation was apparent and, to a lesser extent, with the MTHFR-mutation. For antithrombotic therapy, it was shown that in women with antiphospholipid syndrome and recurrent pregnancy loss, unfractionated heparin plus lowdose aspirin results in significantly better gestational outcome than lowdose aspirin alone. Concerning therapy of women with inherited thrombophilia and pregnancy loss, only small, uncontrolled studies are available, demonstrating improved pregnancy outcome when low molecular weight heparin (LMWH) is used for treatment. In conclusion, heritable thrombophilia and the antiphospholipid-syndrome are major causes of fetal loss after exclusion of other underlying pathologies like chromosomal abnormalities, and screening should be recommended. LMWH with or without aspirin may be used for treatment. There is little value in antenatal screening for prothrombotic polymorphisms to predict the development of small for gestational age infants, preeclampsia or gestational hypertension.
The genetic variability of hepatitis B virus (HBV) represents a challenge for the sensitivity of immunodiagnosis, especially for the detection of surface antigen (HBsAg). There are two types of variants of HBV. Naturally occurring variants are the results of random changes selected over years of population pressure. These variants include HBV genotypes and unusual sequences, which may be poorly detected by immunoassays. The selected variants are mutants that arise in individuals under medically (vaccine, hepatitis B immune globulin and antiviral therapy) or naturally (chronic hepatitis B) induced immune pressure. HBV S-gene mutants have been identified in successfully immunized people worldwide. Based on the assumption that current vaccines containing S protein do not cross-protect against S gene mutants, a mathematical model predicts the disappearance of wild-type HBV in areas with HBsAg endemicity and the emergence of S gene mutants in approximately 100 years as a consequence of universal HBV vaccination. Mutant viruses may escape detection by commercial HBsAg kits. There are several reports on HBsAg negative carriers (HBVDNA positive) of S gene mutants with immunosilent infection or ‘‘unusual’’ serologic constellations. Although S gene mutants have been found to be associated with a more severe clinical course of HBV infection and hepatocellular carcinoma, the clinical significance of the genetic variability of HBV genotypes and HBsAg mutants needs to be further investigated. Detection of HBsAg needs to be improved by the introduction of new HBsAg assays able to recognize S gene mutants described so far and with a lower detection threshold than current immunoassays in order to detect smallest amounts of HBsAg in low-level carriers. There is also a need for more complete epidemiological data on the prevalence of HBsAg mutants in Western Europe and assays for the (differential) screening of mutants need to be developed and evaluated.
The majority of bacterial membrane-bound NiFe-hydrogenases and formate dehydrogenases have homologous membrane-integral cytochrome b subunits. The prototypic NiFe-hydrogenase of Wolinella succinogenes (HydABC complex) catalyzes H2 oxidation by menaquinone during anaerobic respiration and contains a membrane-integral cytochrome b subunit (HydC) that carries the menaquinone reduction site. Using the crystal structure of the homologous FdnI subunit of Escherichia coli formate dehydrogenase-N as a model, the HydC protein was modified to examine residues thought to be involved in menaquinone binding. Variant HydABC complexes were produced in W. succinogenes, and several conserved HydC residues were identified that are essential for growth with H2 as electron donor and for quinone reduction by H2. Modification of HydC with a C-terminal Strep-tag II enabled one-step purification of the HydABC complex by Strep-Tactin affinity chromatography. The tagged HydC, separated from HydAB by isoelectric focusing, was shown to contain 1.9 mol of heme b/mol of HydC demonstrating that HydC ligates both heme b groups. The four histidine residues predicted as axial heme b ligands were individually replaced by alanine in Strep-tagged HydC. Replacement of either histidine ligand of the heme b group proximal to HydAB led to HydABC preparations that contained only one heme b group. This remaining heme b could be completely reduced by quinone supporting the view that the menaquinone reduction site is located near the distal heme b group. The results indicate that both heme b groups are involved in electron transport and that the architecture of the menaquinone reduction site near the cytoplasmic side of the membrane is similar to that proposed for E. coli FdnI.
In Archaea, bacteria, and eukarya, ATP provides metabolic energy for energy-dependent processes. It is synthesized by enzymes known as A-type or F-type ATP synthase, which are the smallest rotatory engines in nature (Yoshida, M., Muneyuki, E., and Hisabori, T. (2001) Nat. Rev. Mol. Cell. Biol. 2, 669-677; Imamura, H., Nakano, M., Noji, H., Muneyuki, E., Ohkuma, S., Yoshida, M., and Yokoyama, K. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 2312-2315). Here, we report the first projected structure of an intact A(1)A(0) ATP synthase from Methanococcus jannaschii as determined by electron microscopy and single particle analysis at a resolution of 1.8 nm. The enzyme with an overall length of 25.9 nm is organized in an A(1) headpiece (9.4 x 11.5 nm) and a membrane domain, A(0) (6.4 x 10.6 nm), which are linked by a central stalk with a length of approximately 8 nm. A part of the central stalk is surrounded by a horizontal-situated rodlike structure ("collar"), which interacts with a peripheral stalk extending from the A(0) domain up to the top of the A(1) portion, and a second structure connecting the collar structure with A(1). Superposition of the three-dimensional reconstruction and the solution structure of the A(1) complex from Methanosarcina mazei Gö1 have allowed the projections to be interpreted as the A(1) headpiece, a central and the peripheral stalk, and the integral A(0) domain. Finally, the structural organization of the A(1)A(0) complex is discussed in terms of the structural relationship to the related motors, F(1)F(0) ATP synthase and V(1)V(0) ATPases.
The signal transducer and activator of transcription (Stat) gene family comprises seven members with similarities in their domain structure and a common mode of activation. Members of this gene family mediate interferon induction of gene transcription and the response to a large number of growth factors and hormones. Extracellular ligand binding to transmembrane receptors causes the intracellular activation of associated tyrosine kinases, phosphorylation of Stat molecules, dimerization, and translocation to the nucleus. Prolactin-induced phosphorylation of Stat5 is a key event in the development and differentiation of mammary epithelial cells. In addition to the crucial phosphorylation at tyrosine 694, we have identified an O-linked N-acetylglucosamine (O-GlcNAc) as another secondary modification essential for the transcriptional induction by Stat5. This modification was only found on nuclear Stat5 after cytokine activation. Similar observations were made with Stat1, Stat3, and Stat6. Glycosylation of Stat5, however, does not seem to be a prerequisite for nuclear translocation. Mass spectrometric analysis revealed a glycosylated peptide in the N-terminal region of Stat5. Replacement of threonine 92 by an alanine residue (Stat5a-T92A) strongly reduced the prolactin induction of Stat5a glycosylation and abolished transactivation of a target gene promoter. Only the glycosylated form of Stat5 was able to bind the coactivator of transcription CBP, an essential interaction for Stat5-mediated gene transcription.
Respiratory chain complex I contains 8-9 iron-sulfur clusters. In several cases, the assignment of these clusters to subunits and binding motifs is still ambiguous. To test the proposed ligation of the tetranuclear iron-sulfur cluster N5 of respiratory chain complex I, we replaced the conserved histidine 129 in the 75-kDa subunit from Yarrowia lipolytica with alanine. In the mutant strain, reduced amounts of fully assembled but destabilized complex I could be detected. Deamino-NADH: ubiquinone oxidoreductase activity was abolished completely by the mutation. However, EPR spectroscopic analysis of mutant complex I exhibited an unchanged cluster N5 signal, excluding histidine 129 as a cluster N5 ligand.
Stable supercomplexes of bacterial respiratory chain complexes III (ubiquinol:cytochrome c oxidoreductase) and IV (cytochrome c oxidase) have been isolated as early as 1985 (Berry, E. A., and Trumpower, B. L. (1985) J. Biol. Chem. 260, 2458-2467). However, these assemblies did not comprise complex I (NADH:ubiquinone oxidoreductase). Using the mild detergent digitonin for solubilization of Paracoccus denitrificans membranes we could isolate NADH oxidase, assembled from complexes I, III, and IV in a 1:4:4 stoichiometry. This is the first chromatographic isolation of a complete “respirasome.” Inactivation of the gene for tightly bound cytochrome c552 did not prevent formation of this supercomplex, indicating that this electron carrier protein is not essential for structurally linking complexes III and IV. Complex I activity was also found in the membranes of mutant strains lacking complexes III or IV. However, no assembled complex I but only dissociated subunits were observed following the same protocols used for electrophoretic separation or chromatographic isolation of the supercomplex from the wild-type strain. This indicates that the P. denitrificans complex I is stabilized by assembly into the NADH oxidase supercomplex. In addition to substrate channeling, structural stabilization of a membrane protein complex thus appears as one of the major functions of respiratory chain supercomplexes.
Arsenic trioxide is a toxic metalloid and carcinogen that is also used as an anticancer drug, and for this reason it is important to identify the routes of arsenite uptake by cells. In this study the ability of hexose transporters to facilitate arsenic trioxide uptake in Saccharomyces cerevisiae was examined. In the absence of glucose, strains with disruption of the arsenite efflux gene ACR3 accumulated high levels of (73)As(OH)(3). The addition of glucose inhibited uptake by approximately 80%. Disruption of FPS1, the aquaglyceroporin gene, reduced glucose-independent uptake by only about 25%, and the residual uptake was nearly completely inhibited by hexoses, including glucose, galactose, mannose, and fructose but not pentoses or disaccharides. A strain lacking FPS1, ACR3, and all genes for hexose permeases except for HXT3, HXT6, HXT7, and GAL2 exhibited hexose-inhibitable (73)As(OH)(3) uptake, whereas a strain lacking all 18 hexose transport-related genes (HXT1 to HXT17 and GAL2), FPS1 and ACR3, exhibited <10% of wild type (73)As(OH)(3) transport. When HXT1, HXT3, HXT4, HXT5, HXT7, or HXT9 was individually expressed in that strain, hexose-inhibitable (73)As(OH)(3) uptake was restored. In addition, the transport of [(14)C]glucose was inhibited by As(OH)(3). These results clearly demonstrate that hexose permeases catalyze the majority of the transport of the trivalent metalloid arsenic trioxide.
Structural and functional characterization of the dimerization region of soluble guanylyl cyclase
(2004)
Soluble guanylyl cyclase (sGC) is a ubiquitous enzyme that functions as a receptor for nitric oxide. Despite the obligate heterodimeric nature of sGC, the sequence segments mediating subunit association have remained elusive. Our initial screening for relevant interaction site(s) in the most common sGC isoenzyme, α1 β1, identified two regions in each subunit, i.e. the regulatory domains and the central regions, contributing to heterodimer formation. To map the relevant segments in the β1 subunit precisely, we constructed multiple N- and C-terminal deletion variants and cotransfected them with full-length α1 in COS cells. Immunoprecipitation revealed that a sequence segment spanning positions 204–408 mediates binding of β1 to α1 The same region of β1[204–408] was found to promote β /β1 homodimerization. Fusion of [204 β1–408] to enhanced green fluorescent protein conferred binding activity to the recipient protein. Coexpression of β1[204–408] with α1 or β1 targeted the sGC subunits for proteasomal degradation, suggesting that β1[204–408] forms structurally deficient complexes with α1 and β1. Analysis of deletion constructs lacking portions of the β1 dimerization region identified two distinct segments contributing to α1 binding, i.e. an N-terminal site covering positions 204–244 and a C-terminal site at 379–408. Both sites are crucial for sGC function because deletion of either site rendered sGC dimerization-deficient and thus functionally inactive. We conclude that the dimerization region of β1 extends over 205 residues of its regulatory and central domains and that two discontinuous sites of 41 and 30 residues, respectively, facilitate binding of β1 to the α1 subunit of sGC.
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the major cytosolic receptor for NO, catalyzing the conversion of GTP to cGMP. In a search for proteins specifically interacting with human sGC, we have identified the multidomain protein AGAP1, the prototype of an ArfGAP protein with a GTPase-like domain, Ankyrin repeats, and a pleckstrin homology domain. AGAP1 binds through its carboxyl terminal portion to both the α1 and β1 subunits of sGC. We demonstrate that AGAP1 mRNA and protein are co-expressed with sGC in human, murine, and rat cells and tissues and that the two proteins interact in vitro and in vivo. We also show that AGAP1 is prone to tyrosine phosphorylation by Src-like kinases and that tyrosine phosphorylation potently increases the interaction between AGAP1 and sGC, indicating that complex formation is modulated by reversible phosphorylation. Our findings may hint to a potential role of AGAP1 in integrating signals from Arf, NO/cGMP, and tyrosine kinase signaling pathways.
Nitric oxide (NO) represents a short lived mediator that pivotally drives keratinocyte movements during cutaneous wound healing. In this study, we have identified p68 DEAD box RNA helicase (p68) from an NO-induced differential keratinocyte cDNA library. Subsequently, we have analyzed regulation of p68 by wound-associated mediators in human and murine keratinocytes. NO, serum, growth factors, and pro-inflammatory cytokines were potent inducers of p68 expression in the cells. p68 was constitutively expressed in the epithelial compartment of murine skin. Upon injury, we found a transient down-regulation of overall p68 protein in wound tissue. However, p68 did not completely disappear during early wound repair, as we found an expression of p68 protein in isolated wound margin tissue 24 h after wounding. Moreover, immunohistochemistry and cell fractionation analysis revealed a restricted localization of p68 in keratinocyte nuclei of the developing epithelium. Accordingly, cultured keratinocytes also showed a nuclear localization of the helicase. Moreover, confocal microscopy revealed a strong localization of p68 protein within the nucleoli of the cells. Functional analyses demonstrated that p68 strongly participated in keratinocyte proliferation and gene expression. Keratinocytes that constitutively overexpressed p68 protein were characterized by a marked increase in serum-induced proliferation and vascular endothelial growth factor expression, whereas down-regulation of endogenous p68 using small interfering RNA markedly attenuated serum-induced proliferation and vascular endothelial growth factor expression. Altogether, our results suggest a tightly controlled expression and nucleolar localization of p68 in keratinocytes in vitro and during skin repair in vivo that functionally contributes to keratinocyte proliferation and gene expression.
The MAM (meprin/A5-protein/PTPmu) domain is present in numerous proteins with diverse functions. PTPμ belongs to the MAM-containing subclass of protein-tyrosine phosphatases (PTP) able to promote cell-to-cell adhesion. Here we provide experimental evidence that the MAM domain is a homophilic binding site of PTPμ. We demonstrate that the MAM domain forms oligomers in solution and binds to the PTPμ ectodomain at the cell surface. The presence of two disulfide bridges in the MAM molecule was evidenced and their integrity was found to be essential for MAM homophilic interaction. Our data also indicate that PTPμ ectodomain forms oligomers and mediates the cellular adhesion, even in the absence of MAM domain homophilic binding. Reciprocally, MAM is able to interact homophilically in the absence of ectodomain trans binding. The MAM domain therefore contains independent cis and trans interaction sites and we predict that its main role is to promote lateral dimerization of PTPμ at the cell surface. This finding contributes to the understanding of the signal transduction mechanism in MAM-containing PTPs.
Supersilylated tetrachlorodigermane (tBu3Si)Cl2GeGeCl2(SitBu3) and trigermoxetane (tBu3Si)3Ge3Cl3O
(2004)
In contrast to the tetrachlorodigermane (tBu3Si)Cl2Ge-GeCl2(SitBu3), the cis,transcyclotrigermane (tBu3SiGeCl)3 is sensitive to oxygen. Its treatment with O2 at ambient temperature leads to the trigermoxetane (tBu3Si)3Ge3Cl3O. According to an X-ray structure analysis of single crystals consisting of cocrystallized (tBu3Si)3Ge3Cl3O and (tBu3Si)Cl2Ge-GeCl2(SitBu3) the trigermaoxetane contains an almost planar Ge3O-ring while the tetrachlorodigermane (tBu3Si)Cl2Ge- GeCl2(SitBu3) possesses a Si-Ge-Ge-Si chain which is exactly all trans,
The major light-harvesting complex (LHC-II) of higher plants plays a crucial role in capturing light energy for photosynthesis and in regulating the flow of energy within the photosynthetic apparatus. Native LHC-II isolated from plant tissue consists of three isoforms, Lhcb1, Lhcb2, and Lhcb3, which form homo- and heterotrimers. All three isoforms are highly conserved among different species, suggesting distinct functional roles. We produced the three LHC-II isoforms by heterologous expression of the polypeptide in Escherichia coli and in vitro refolding with purified pigments. Although Lhcb1 and Lhcb2 are very similar in polypeptide sequence and pigment content, Lhcb3 is clearly different because it lacks an N-terminal phosphorylation site and has a higher chlorophyll a/b ratio, suggesting the absence of one chlorophyll b. Low temperature absorption and fluorescence emission spectra of the pure isoforms revealed small but significant differences in pigment organization. The oligomeric state of the pure isoforms and of their permutations was investigated by native gel electrophoresis, sucrose density gradient centrifugation, and SDS-PAGE. Lhcb1 and Lhcb2 formed trimeric complexes by themselves and with one another, but Lhcb3 was able to do so only in combination with one or both of the other isoforms. We conclude that the main role of Lhcb1 and Lhcb2 is in the adaptation of photosynthesis to different light regimes. The most likely role of Lhcb3 is as an intermediary in light energy transfer from the main Lhcb1/Lhcb2 antenna to the photosystem II core.
The transporter associated with antigen processing (TAP1/2) translocates cytosolic peptides of proteasomal degradation into the endoplasmic reticulum (ER) lumen. A peptide-loading complex of tapasin, major histocompatibility complex class I, and several auxiliary factors is assembled at the transporter to optimize antigen display to cytotoxic T-lymphocytes at the cell surface. The heterodimeric TAP complex has unique N-terminal domains in addition to a 6 + 6-transmembrane segment core common to most ABC transporters. Here we provide direct evidence that this core TAP complex is sufficient for (i) ER targeting, (ii) heterodimeric assembly within the ER membrane, (iii) peptide binding, (iv) peptide transport, and (v) specific inhibition by the herpes simplex virus protein ICP47 and the human cytomegalovirus protein US6. We show for the first time that the translocation pore of the transporter is composed of the predicted TM-(5-10) of TAP1 and TM-(4-9) of TAP2. Moreover, we demonstrate that the N-terminal domains of TAP1 and TAP2 are essential for recruitment of tapasin, consequently mediating assembly of the macromolecular peptide-loading complex.
The purification and functional reconstitution of a five-component oligopeptide ATP-binding cassette transporter with a remarkably wide substrate specificity are described. High-affinity peptide uptake was dependent on liganded substrate-binding protein OppA, which interacts with the translocator OppBCDF with higher affinity than unliganded OppA. Transport screening with combinatorial peptide libraries revealed that (i) the Opp transporter is not selective with respect to amino acid side chains of the transported peptides; (ii) any peptide that can bind to OppA is transported via Opp, including very long peptides up to 35 residues long; and (iii) the binding specificity of OppA largely determines the overall transport selectivity.
The mode of the antitumoral activity of multimutated oncolytic herpes simplex virus type 1 G207 has not been fully elucidated yet. Because the antitumoral activity of many drugs involves the inhibition of tumor blood vessel formation, we determined if G207 had an influence on angiogenesis. Monolayers of human umbilical vein endothelial cells and human dermal microvascular endothelial cells, but not human dermal fibroblasts, bronchial epithelial cells, and retinal glial cells, were highly sensitive to the replicative and cytotoxic effects of G207. Moreover, G207 infection caused the destruction of endothelial cell tubes in vitro. In the in vivo Matrigel plug assay in mice, G207 suppressed the formation of perfused vessels. Intratumoral treatment of established human rhabdomyosarcoma xenografts with G207 led to the destruction of tumor vessels and tumor regression. Ultrastructural investigations revealed the presence of viral particles in both tumor and endothelial cells of G207-treated xenografts, but not in adjacent normal tissues. These findings show that G207 may suppress tumor growth, in part, due to inhibition of angiogenesis.
We study issues of duality in 3D field theory models over a canonical noncommutative spacetime and obtain the noncommutative extension of the self-dual model induced by the Seiberg–Witten map. We apply the dual projection technique to uncover some properties of the noncommutative Maxwell–Chern–Simons theory up to first-order in the noncommutative parameter. A duality between this theory and a model similar to the ordinary self-dual model is established. The correspondence of the basic fields is obtained and the equivalence of algebras and equations of motion are directly verified. We also comment on previous results in this subject.
We perform a study of the possible existence of hybrid stars with color superconducting quark cores using a specific hadronic model in a combination with an NJL-type quark model. It is shown that the constituent mass of the non-strange quarks in vacuum is a very important parameter that controls the beginning of the hadron–quark phase transition. At relatively small values of the mass, the first quark phase that appears is the two-flavor color superconducting (2SC) phase which, at larger densities, is replaced by the color-flavor locked (CFL) phase. At large values of the mass, on the other hand, the phase transition goes from the hadronic phase directly into the CFL phase avoiding the 2SC phase. It appears, however, that the only stable hybrid stars obtained are those with the 2SC quark cores.