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Molecular proximity of Kv1.3 voltage-gated potassium channels and beta(1)-integrins on the plasma membrane of melanoma cells: effects of cell adherence and channel blockers 下载免费PDF全文
Tumor cell membranes have multiple components that participate in the process of metastasis. The present study investigates the physical association of beta1-integrins and Kv1.3 voltage-gated potassium channels in melanoma cell membranes using resonance energy transfer (RET) techniques. RET between donor-labeled anti-beta1-integrin and acceptor-labeled anti-Kv1.3 channels was detected on LOX cells adherent to glass and fibronectin-coated coverslips. However, RET was not observed on LOX cells in suspension, indicating that molecular proximity of these membrane molecules is adherence-related. Several K(+) channel blockers, including tetraethylammonium, 4-aminopyridine, and verapamil, inhibited RET between beta1-integrins and Kv1.3 channels. However, the irrelevant K(+) channel blocker apamin had no effect on RET between beta1-integrins and Kv1.3 channels. Based on these findings, we speculate that the lateral association of Kv1.3 channels with beta1-integrins contributes to the regulation of integrin function and that channel blockers might affect tumor cell behavior by influencing the assembly of supramolecular structures containing integrins. 相似文献
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Łukasz Jaremko Mariusz Jaremko Paweł Pasikowski Marek Cebrat Piotr Stefanowicz Marek Lisowski Jolanta Artym Michał Zimecki Igor Zhukov Zbigniew Szewczuk 《Biopolymers》2009,91(6):423-431
Recently, ubiquitin was suggested as a promising anti‐inflammatory protein therapeutic. We found that a peptide fragment corresponding to the ubiquitin50–59 sequence (LEDGRTLSDY) possessed the immunosuppressive activity comparable with that of ubiquitin. CD and NMR spectroscopies were used to determine the conformational preferences of LEDGRTLSDY in solution. The peptide mixture, obtained by pepsin digestion of ubiquitin, was even more potent than the intact protein. Although the peptide exhibited a well‐defined conformation in methanol, its structure was distinct from the corresponding 50–59 fragment in the native ubiquitin molecule. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 423–431, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com 相似文献
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Pasikowski P Goździewicz T Stefanowicz P Artym J Zimecki M Szewczuk Z 《Peptides》2011,32(12):2418-2427
Ubiquitin is a conservative polypeptide present in every eukaryotic cell. Apart from its involvement in proteasomal degradation and other intracellular signal pathways, it was suggested to play an important role as the extracellular immunomodulator and antimicrobial agent. Moreover, ubiquitin-derived peptides were shown to express significant biological activities. Our previous studies showed a high immunosuppressive potency of the ubiquitin peptic hydrolysate in which we identified over 70 different peptides. The present work focuses on synthesizing the most abundant of these peptides and investigating their immunomodulatory potency. The peptide VKTLTGKTI possessed the highest immunosuppressory activity in AFC experiments, comparable to the previously described LEDGRTLSDY sequence (a previously discovered ubiquitin-derived peptide). Moreover, some of the investigated peptides expressed immunostimulatory effects. These findings support the idea that ubiquitin, together with products of its degradation, could represent a self-regulating immunoregulatory system. Peptide VKTLTGKTI was also tested for its activity to prolong the skin graft survival in mice. The results showed that the investigated peptide significantly extended the skin transplant rejection time, therefore it could be considered as a potential supplementary medicine in the post-transplantation therapy. Moreover, we synthesized two analogs of investigated peptides, first designed to mimic the non-linear epitope consisting of ubiquitin 16-21 and ubiquitin 52-57 fragments, and second designed to mimic the ubiquitin 5-13 hairpin. We also tested their immunosuppressory activity in in vitro experiments. 相似文献
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Aruna Kasoju M Lakshmi Narasu Charuvaka Muvva Bathula VV SubbaRao 《Bioinformation》2012,8(14):684-686
Aflatoxins are polyketide-derived secondary metabolites produced by Aspergillus spp. The toxic effects of aflatoxins have adverse
consequences for human health and agricultural economics. The aflR gene, a regulatory gene for aflatoxin biosynthesis, encodes a
protein containing a zinc-finger DNA-binding motif. AFLR-Protein three-dimensional model was generated using Robetta server.
The modeled AFLR-Protein was further optimization and validation using Rampage. In the simulations, we monitored the
backbone atoms and the C-α-helix of the modeled protein. The low RMSD and the simulation time indicate that, as expected, the
3D structural model of AFLR-protein represents a stable folding conformation. This study paves the way for generating computer
molecular models for proteins whose crystal structures are not available and which would aid in detailed molecular mechanism of
inhibition of aflatoxin. 相似文献
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Michał Zimecki Jolanta Artym Maja Kocięba Krystian Pluta Beata Morak-Młodawska Małgorzata Jeleń 《Cellular & molecular biology letters》2009,14(4):622-635
In this study, we evaluated the activities of new types of azaphenothiazines in the following immunological assays: the proliferative
response of human peripheral blood mononuclear cells induced by phytohemagglutin A or anti-CD3 antibodies; lipopolysaccharide-induced
cytokine production by human PBMC; the secondary, humoral immune response in mice to sheep erythrocytes (in vitro); and delayed-type hypersensitivity in mice to ovalbumin (in vivo). In some tests, chlorpromazine served as a reference drug. The compounds exhibited differential inhibitory activities in
the proliferation tests, with 10H-2,7-diazaphenothiazine (compound 1) and 6-(3-dimethylaminopropyl)diquinothiazine (compound 8) being most suppressive. Compound 1 was selected for further studies, and was found to be strongly suppressive in the humoral
immune response even at low concentrations (1 μg/ml). Compound 1 also inhibited the delayed-type hypersensitivity lipopolysaccharide-induced production of tumor necrosis factor and interleukin-6
in cultures of human blood cells. As there were only two subjects in this study, the effects of these compounds on human blood
cells need to be confirmed. In this paper, we also discuss the structure-activity relationships of selected compounds. 相似文献
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Bharti S Inoue H Bharti K Hirsch DS Nie Z Yoon HY Artym V Yamada KM Mueller SC Barr VA Randazzo PA 《Molecular and cellular biology》2007,27(23):8271-8283
Invadopodia are Src-induced cellular structures that are thought to mediate tumor invasion. ASAP1, an Arf GTPase-activating protein (GAP) containing Src homology 3 (SH3) and Bin, amphiphysin, and RVS161/167 (BAR) domains, is a substrate of Src that controls invadopodia. We have examined the structural requirements for ASAP1-dependent formation of invadopodia and related structures in NIH 3T3 fibroblasts called podosomes. We found that both predominant splice variants of ASAP1 (ASAP1a and ASAP1b) associated with invadopodia and podosomes. Podosomes were highly dynamic, with rapid turnover of both ASAP1 and actin. Reduction of ASAP1 levels by small interfering RNA blocked formation of invadopodia and podosomes. Podosomes were formed in NIH 3T3 fibroblasts in which endogenous ASAP1 was replaced with either recombinant ASAP1a or ASAP1b. ASAP1 mutants that lacked the Src binding site or GAP activity functioned as well as wild-type ASAP1 in the formation of podosomes. Recombinant ASAP1 lacking the BAR domain, the SH3 domain, or the Src phosphorylation site did not support podosome formation. Based on these results, we conclude that ASAP1 is a critical target of tyrosine kinase signaling involved in the regulation of podosomes and invadopodia and speculate that ASAP1 may function as a coincidence detector of simultaneous protein association through the ASAP1 SH3 domain and phosphorylation by Src. 相似文献
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Visualization of molecular structures aids in the understanding of structural and functional roles of biological macromolecules.
Macromolecular transport between the cell nucleus and cytoplasm is facilitated by the nuclear pore complex (NPC). The ring
structure of the NPC is large and contains several distinct proteins (nucleoporins) which function as a selective gate for the passage
of certain molecules into and out of the nucleus. In this note we demonstrate the utility of a python code that allows direct
mapping of the physiochemical properties of the constituent nucleoporins on the scaffold of the yeast NPC׳s cytoplasmic view. We
expect this tool to be useful for researchers to visualize the NPC based on their physiochemical properties and how it alters when
specific mutations are introduced in one or more of the nucleoporins. The code developed using Python is available freely from the
authors. 相似文献
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Michał Zimecki Jolanta Artym Maja Kocięba Beata Weber-Dąbrowska Jan Borysowski Andrzej Górski 《BMC microbiology》2009,9(1):169-8