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71.
Reid CM Ebikeme C Barrett MP Patzewitz EM Müller S Robins DJ Sutherland A 《Bioorganic & medicinal chemistry letters》2008,18(20):5399-5401
Efficient synthetic routes have been developed for the preparation of two new polyazamacrocycles tagged with structural motifs recognised by the Trypanosoma brucei P2 aminopurine transporter. Biological testing of these compounds showed highly selective anti-protozoal activity against trypanosomes. 相似文献
72.
Rosemeyer H Stürenberg EM Herdewijn P 《Nucleosides, nucleotides & nucleic acids》2007,26(8-9):995-999
Four different series of nucleolipids or bola-nucleolipids were synthesized or re-synthesized. Most of the compounds were studied with respect to their gelation properties toward either water or aromatic, hetero-aromatic, and aliphatic hydrocarbons. Bola-nucleolipids 6 and 7 do not gelate any solvent tested, neither as sole additive nor by adding up to 10 wt% of a 1:1 mixture. The nucleolipid 22 carrying the antiviral acyclovir as a head group proved to be a potent organogelator for aromatic hydrocarbons such as toluene, but not for hetarenes, aliphatic hydrocarbons or water. The mono-tailed nucleolipid 24 exhibits excellent organogelator properties for both aromatic and aliphatic hydrocarbons. These were studied as a function of concentration and temperature. 相似文献
73.
Casal E Federici L Zhang W Fernandez-Recio J Priego EM Miguel RN DuHadaway JB Prendergast GC Luisi BF Laue ED 《Biochemistry》2006,45(43):12917-12928
BAR domains are found in proteins that bind and remodel membranes and participate in cytoskeletal and nuclear processes. Here, we report the crystal structure of the BAR domain from the human Bin1 protein at 2.0 A resolution. Both the quaternary and tertiary architectures of the homodimeric Bin1BAR domain are built upon "knobs-into-holes" packing of side chains, like those found in conventional left-handed coiled-coils, and this packing governs the curvature of a putative membrane-engaging concave face. Our calculations indicate that the Bin1BAR domain contains two potential sites for protein-protein interactions on the convex face of the dimer. Comparative analysis of structural features reveals that at least three architectural subtypes of the BAR domain are encoded in the human genome, represented by the Arfaptin, Bin1/Amphiphysin, and IRSp53 BAR domains. We discuss how these principal groups may differ in their potential to form regulatory heterotypic interactions. 相似文献
74.
Khlistunova I Biernat J Wang Y Pickhardt M von Bergen M Gazova Z Mandelkow E Mandelkow EM 《The Journal of biological chemistry》2006,281(2):1205-1214
We generated several cell models of tauopathy in order to study the mechanisms of neurodegeneration in diseases involving abnormal changes of tau protein. N2a neuroblastoma cell lines were created that inducibly express different variants of the repeat domain of tau (tau(RD)) when exposed to doxycycline (Tet-On system). The following three constructs were chosen: (i) the repeat domain of tau that coincides with the core of Alzheimer paired helical filaments; (ii) the repeat domain with the deletion mutation DeltaK280 known from frontotemporal dementia and highly prone to spontaneous aggregation; and (iii) the repeat domain with DeltaK280 and two proline point mutations that inhibit aggregation. The comparison of wild-type, pro-aggregation, and anti-aggregation mutants shows the following. (a) Aggregation of tau(RD) is toxic to cells. (b) The degree of aggregation and toxicity depends on the propensity for beta-structure. (c) Soluble mutants of tau(RD) that cannot aggregate are not toxic. (d) Aggregation is preceded by fragmentation. (e) Fragmentation of tau(RD) in cells is initially due to a thrombin-like protease activity. (f) Phosphorylation of tau(RD) (at KXGS motifs) precedes aggregation but is not correlated with the degree of aggregation. (g) Aggregates of tau(RD) disappear when the expression is silenced, showing that aggregation is reversible. (h) Aggregation can be prevented by drugs and even pre-formed aggregates can be dissolved again by drugs. Thus, the cell models open up new insights into the relationship between the structure, expression, phosphorylation, aggregation, and toxicity of tau(RD) that can be used to test current hypotheses on tauopathy and to develop drugs that prevent the aggregation and degeneration of cells. 相似文献
75.
Bringmann G Feineis D Münchbach M God R Peters K Peters EM Mössner R Lesch KP 《Zeitschrift für Naturforschung. C, Journal of biosciences》2006,61(7-8):601-610
Chloral-derived beta-carbolines, which are structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 5), are discussed to contribute to neuronal cell death in idiopathic Parkinson's disease. The cytotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 4) to neuronal-like clonal pheochromocytoma PC12 cells was examined by the determination of lactate dehydrogenase (LDH) release. After incubation for 48 h, 4 showed a strong dose-dependent cytotoxic activity towards PC12 cells with an ED50 value of 230 microM. In PC12 cells reductive dehalogenation of 4 was observed giving rise to the formation of 1-dichloromethyl-1,2,3,4-tetrahydro-beta-carboline (6) as a main TaClo metabolite exhibiting a cytotoxic potential comparable to that of TaClo. An X-ray structure analysis, performed for the trifluoroacetyl derivative of 6, revealed the N-substituent of such a highly chlorinated agent to be dramatically pushed out of the beta-carboline ring 'plane' due to the high steric demand of the huge dichloromethyl group at C(1). 相似文献
76.
77.
Eva-Maria Ladenburger Ivonne M. Sehring Iris Korn Helmut Plattner 《Molecular and cellular biology》2009,29(13):3605-3622
A database search of the Paramecium genome reveals 34 genes related to Ca2+-release channels of the inositol-1,4,5-trisphosphate (IP3) or ryanodine receptor type (IP3R, RyR). Phylogenetic analyses show that these Ca2+ release channels (CRCs) can be subdivided into six groups (Paramecium tetraurelia CRC-I to CRC-VI), each one with features in part reminiscent of IP3Rs and RyRs. We characterize here the P. tetraurelia CRC-IV-1 gene family, whose relationship to IP3Rs and RyRs is restricted to their C-terminal channel domain. CRC-IV-1 channels localize to cortical Ca2+ stores (alveolar sacs) and also to the endoplasmic reticulum. This is in contrast to a recently described true IP3 channel, a group II member (P. tetraurelia IP3RN-1), found associated with the contractile vacuole system. Silencing of either one of these CRCs results in reduced exocytosis of dense core vesicles (trichocysts), although for different reasons. Knockdown of P. tetraurelia IP3RN affects trichocyst biogenesis, while CRC-IV-1 channels are involved in signal transduction since silenced cells show an impaired release of Ca2+ from cortical stores in response to exocytotic stimuli. Our discovery of a range of CRCs in Paramecium indicates that protozoans already have evolved multiple ways for the use of Ca2+ as signaling molecule.Ca2+ is an important component of cell activity in all organisms, from protozoa to mammals. Thereby Ca2+ may originate from the outside medium and/or from internal stores (7, 18). Ca2+ release from internal stores is mediated by various Ca2+ release channels (CRCs), of which the inositol-1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) families have been studied most extensively (8, 9, 29, 63). IP3Rs and RyRs have been identified in various metazoan organisms (reviewed in references 9, 28, and 104). According to these reviews, there exist three genetically distinct isoforms of each receptor type in mammals and orthologues have been identified in various nonmammalian vertebrates, e.g., frogs, chickens, and fish. RyRs and IP3Rs were also cloned and sequenced in the invertebrates Drosophila melanogaster and Caenorhabditis elegans, which possess one copy of each receptor type.Functional evidence for Ca2+ release in response to ryanodine or IP3 receptor agonists has been described in several unicellular systems. Treatment of permeabilized Plasmodium chabaudi parasites with IP3 results in Ca2+ release, which is inhibited by the IP3 receptor antagonist heparin (69). Another apicomplexan parasite, Toxoplasma gondii, responds to agonists and antagonists of both, ryanodine and IP3 receptors, by mediating increases in intracellular Ca2+ concentration ([Ca2+]i) (56). Stimulation of Trypanosoma cruzi with carbachol results in increased [Ca2+]i and IP3 (59). IP3 and cyclic ADP-ribose induces Ca2+ release in Euglena gracilis microsome fractions in a dose-dependent manner (61). In the giant algae Chara corallina and Nitrella translucens, IP3 produces action potentials involving increased [Ca2+]i (93). Treatment of vacuolar membrane vesicles from Candida albicans with IP3 results in Ca2+ release, blocked by heparin and ruthenium red (14). IP3 generates and maintains a Ca2+ gradient in the hyphal tip of Neurospora crassa and the IP3-sensitive channels have been reconstituted and characterized with the planar bilayer method (87). In summary, these publications suggest that IP3-dependent signaling pathways are conserved among unicellular organisms, including protozoa.Despite these data, the molecular characterization of IP3 or ryanodine receptors in low eukaryotes is currently a challenge since the identification of orthologues has not been possible thus far, probably because of evolutionary sequence divergence (66). Traynor et al. (96) identified an IP3 receptor-like protein, IplA, in Dictyostelium discoideum, which possesses regions related to IP3R sequences, but thus far no evidence for IP3 interaction exists. We have recently described an IP3R in the ciliated protozoa Paramecium tetraurelia (referred to here as P. tetraurelia IP3RN) (53), with features characteristic of mammalian IP3Rs in terms of topology and ability for IP3 binding. The expression level of P. tetraurelia IP3RN is modulated by extracellular Ca2+ concentrations ([Ca2+]o) and immunofluorescence studies reveal an unexpected localization to the contractile vacuole complex (CVC), the major organelle involved in osmoregulation (2). The ionic composition of the contractile vacuole fluid by ion-selective microelectrodes (91) suggests that the organelle plays a major role in expelling an excess of cytosolic Ca2+. Therefore, these IP3Rs may here mediate a latent, graded reflux of Ca2+ for fine-tuning of [Ca2+]i and thus serve [Ca2+] homeostasis (53).Besides [Ca2+] homeostasis, the Paramecium cell has to regulate a variety of well-characterized processes (75). This includes exocytosis of dense-core secretory vesicles (trichocysts) (71, 74, 99). Each cell possesses up to 1,000 trichocysts attached to the cell membrane. Their contents can be extruded synchronously in response to natural stimuli, i.e., predators (34, as confirmed by Knoll et al. [49]), to artificial polyamine secretagogues such as aminoethyldextran (AED) (78), to caffeine (48) or to the ryanodine substitute, 4-chloro-meta-cresol (4-CmC) (46). Their expulsion strictly depends on Ca2+ (10) and is accompanied by an increase of intracellular [Ca2+]i (24, 47). This Ca2+ signal originates from rapid mobilization of cortical stores, the alveolar sacs (33, 64, 74), superimposed by Ca2+ influx (46, 72). It thus represents a SOC-type mechanism (SOC, store-operated Ca2+ entry) known from mammalian systems (81).Upon exocytosis stimulation ∼60% of their total Ca2+ is released from alveolar sacs (33). These are Ca2+ stores (90) represented by flat membrane compartments tightly attached at the cell membrane surrounding each trichocyst docking site. They possess a SERCA-type pump located at the membrane facing the cell center (36, 37) and a luminal high-capacity/low-affinity CaBP of the calsequestrin type (73). Thus far, Ca2+ release channels of these stores were identified only indirectly as cells respond by exocytosis to the RyR activators caffeine (54, 48) and 4-CmC (46). However, an involvement of conserved RyRs has remained questionable as ryanodine is not able to activate Ca2+ release from alveolar sacs, as is the case with IP3 (54). Therefore, one of the most intriguing questions is the elucidation of the molecular nature of the channels mediating Ca2+ release from alveolar sacs upon stimulated exocytosis.In the present work we describe a novel family of CRCs (P. tetraurelia CRC-IV-1), whose members display several properties of the channels postulated above. In detail, the identified CRC-IV-1 channels localize to the alveolar sacs. Functional and fluorochrome analyses after gene silencing reveal that they are essential for mediating Ca2+ release and exocytosis in response to AED, caffeine, or 4-CmC. Their classification as “novel” CRC type is based on a restricted relationship to the C-terminal channel domains of IP3Rs and RyRs. The overall size and the number of putative transmembrane domains resemble IP3Rs, but N-terminal parts of CRC-IV-1 channels do not show any conservation, such as an IP3-binding domain. Therefore, CRC-IV-1 channels represent distant relatives of IP3Rs and RyRs and may belong to an ancestral Ca2+ signaling pathway. 相似文献
78.
Goldsbury C Mocanu MM Thies E Kaether C Haass C Keller P Biernat J Mandelkow E Mandelkow EM 《Traffic (Copenhagen, Denmark)》2006,7(7):873-888
Amyloid-beta, a peptide derived from the precursor protein APP, accumulates in the brain and contributes to the neuropathology of Alzheimer's disease. Increased generation of amyloid-beta might be caused by axonal transport inhibition, via increased dwell time of APP vesicles and thereby higher probability of APP cleavage by secretase enzymes residing on the same vesicles. We tested this hypothesis using a neuronal cell culture model of inhibited axonal transport and by imaging vesicular transport of fluorescently tagged APP and beta-secretase (BACE1). Microtubule-associated tau protein blocks vesicle traffic by inhibiting the access of motor proteins to the microtubule tracks. In neurons co-transfected with CFP-tau, APP-YFP traffic into distal neurites was strongly reduced. However, this did not increase amyloid-beta levels. In singly transfected axons, APP-YFP was transported in large tubules and vesicles moving very fast (on average 3 microm/s) and with high fluxes in the anterograde direction (on average 8.4 vesicles/min). By contrast, BACE1-CFP movement was in smaller tubules and vesicles that were almost 2x slower (on average 1.6 microm/s) with approximately 18x lower fluxes (on average 0.5 vesicles/min). Two-colour microscopy of co-transfected axons confirmed that the two proteins were sorted into distinct carriers. The results do not support the above hypothesis. Instead, they indicate that APP is transported on vesicles distinct from the secretase components and that amyloid-beta is not generated in transit when transport is blocked by tau. 相似文献
79.
80.
Timm T Li XY Biernat J Jiao J Mandelkow E Vandekerckhove J Mandelkow EM 《The EMBO journal》2003,22(19):5090-5101
MARK, a kinase family related to PAR-1 involved in establishing cell polarity, phosphorylates microtubule-associated proteins (tau/MAP2/MAP4) at KXGS motifs, causes detachment from microtubules, and their disassembly. The sites are prominent in tau from Alzheimer's disease brains. We studied the activation of MARK and identified the upstream kinase, MARKK, a member of the Ste20 kinase family. It phosphorylates MARK within the activation loop (T208 in MARK2). A fraction of MARK in brain tissue is doubly phosphorylated (at T208/S212), reminiscent of the activation of MAP kinase; however, the phosphorylation of the second site in MARK (S212) is inhibitory. In cells the activity of MARKK enhances microtubule dynamics through the activation of MARK and leads to phosphorylation and detachment of tau or equivalent MAPs from microtubules. Overexpression of MARK eventually leads to microtubule breakdown and cell death, but in neuronal cells the primary effect is to allow the development of neurites during differentiation. 相似文献