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81.
Ohne Zusammenfassung 相似文献
82.
PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin 下载免费PDF全文
Matenia D Griesshaber B Li XY Thiessen A Johne C Jiao J Mandelkow E Mandelkow EM 《Molecular biology of the cell》2005,16(9):4410-4422
MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the down-regulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin- and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks. 相似文献
83.
Myosin-V, Kinesin-1, and Kinesin-3 cooperate in hyphal growth of the fungus Ustilago maydis 下载免费PDF全文
Schuchardt I Assmann D Thines E Schuberth C Steinberg G 《Molecular biology of the cell》2005,16(11):5191-5201
Long-distance transport is crucial for polar-growing cells, such as neurons and fungal hyphae. Kinesins and myosins participate in this process, but their functional interplay is poorly understood. Here, we investigate the role of kinesin motors in hyphal growth of the plant pathogen Ustilago maydis. Although the microtubule plus-ends are directed to the hyphal tip, of all 10 kinesins analyzed, only conventional kinesin (Kinesin-1) and Unc104/Kif1A-like kinesin (Kinesin-3) were up-regulated in hyphae and they are essential for extended hyphal growth. deltakin1 and deltakin3 mutant hyphae grew irregular and remained short, but they were still able to grow polarized. No additional phenotype was detected in deltakin1rkin3 double mutants, but polarity was lost in deltamyo5rkin1 and deltamyo5rkin3 mutant cells, suggesting that kinesins and class V myosin cooperate in hyphal growth. Consistent with such a role in secretion, fusion proteins of green fluorescent protein and Kinesin-1, Myosin-V, and Kinesin-3 accumulate in the apex of hyphae, a region where secretory vesicles cluster to form the fungal Spitzenk?rper. Quantitative assays revealed a role of Kin3 in secretion of acid phosphatase, whereas Kin1 was not involved. Our data demonstrate that just two kinesins and at least one myosin support hyphal growth. 相似文献
84.
Antagonist and agonist binding models of the human gonadotropin-releasing hormone receptor 总被引:2,自引:0,他引:2
Söderhäll JA Polymeropoulos EE Paulini K Günther E Kühne R 《Biochemical and biophysical research communications》2005,333(2):568-582
G-protein-coupled receptors (GPCRs) constitute one of the most important classes of drug targets. Since the first high-resolution structure of a GPCR was determined by Palczewski and co-workers [K. Palczewski, T. Kumasaka, T. Hori, C.A. Behnke, H. Motoshima, B.A. Fox, I. Le Trong, D.C. Teller, T. Okada, R.E. Stenkamp, M. Yamamoto, M. Miyano, Crystal structure of rhodopsin: a G-protein-coupled receptor, Science 289 (2000) 739-745], development of in silico models of rhodopsin-like GPCRs could be rationally founded. In this work, we present a model of the human gonadotropin-releasing hormone receptor based on the rhodopsin structure. The transmembrane helices are modeled by homology, while the extra- and intra-cellular loops are modeled in such a way that experimentally determined interactions and microdomains (e.g., hydrophobic cores) are retained. We conclude that specifically tailored models, compared to more automatic approaches, have the benefit that known interactions are easily introduced early in the homology modeling. Furthermore, tailored models, although more tedious to construct, are better suited for drug lead finding and for compound optimization. To test the stability of the receptor, we performed a 1 ns molecular dynamics simulation. Moreover, we docked two agonists (native GnRH and Triptorelin, [dTrp(6)]-GnRH) and two antagonists (Cetrorelix, dNal(1)-dCpa(2)-dPal(3)-Ser(4)-Tyr(5)-dCit(6)-Leu(7)-Arg(8)-Pro(9)-dAla(10)), and the covalently constrained dicyclic decapeptide dicyclo(1,1'-5/4-10)[Ac-Glu(1)(Gly(1)')-dCpa(2)-dTrp(3)-Asp(4)-dbu(5)-dNal(6)-Leu(7)-Arg(8)-Pro(9)-dpr(10)-NH(2)] into the putative receptor binding site. The docked ligand conformations result in ligand-receptor interactions that are generally in good agreement with site-directed mutagenesis and ligand-binding studies presented in the literature. Our results indicate that the binding conformation of the antagonists differs from that of the agonists. This difference can be linked to the activation or inhibition of the receptor. 相似文献
85.
Nishimura H Yajima T Muta H Podack ER Tani K Yoshikai Y 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(7):4627-4634
Memory CD8+ T cells can be divided into two subsets, central memory (T(CM)) and effector memory (T(EM)) CD8+ T cells. We found that CD30, a member of the TNFR-associated factor (TRAF)-linked TNFR superfamily, signaling is involved in differentiation of long-lived CD8+ T(CM) cells following Listeria monocytogenes infection. Although CD8+ T(EM) cells transiently accumulated in the nonlymphoid tissues of CD30 ligand (CD153-/-) mice after infection, long-lived memory CD8+ T(CM) cells were poorly generated in these mice. CCR7 mRNA expression was down-regulated in CD8+ T cells of the spleen of CD153-/- mice in vivo and the expression was up-regulated in CD8+ T(EM) cells by anti-CD30 mAb cross-linking in vitro. These results suggest that CD30/CD30 ligand signaling plays an important role in the generation of long-lived memory CD8+ T cells at least partly by triggering homing receptors for T(CM) cells. 相似文献
86.
Bafunno V Giancaspero TA Brizio C Bufano D Passarella S Boles E Barile M 《The Journal of biological chemistry》2004,279(1):95-102
We have studied the functional steps by which Saccharomyces cerevisiae mitochondria can synthesize FAD from cytosolic riboflavin (Rf). Riboflavin uptake into mitochondria took place via a mechanism that is consistent with the existence of (at least two) carrier systems. FAD was synthesized inside mitochondria by a mitochondrial FAD synthetase (EC 2.7.7.2), and it was exported into the cytosol via an export system that was inhibited by lumiflavin, and which was different from the riboflavin uptake system. To understand the role of the putative mitochondrial FAD carrier, Flx1p, in this pathway, an flx1Delta mutant strain was constructed. Coupled mitochondria isolated from flx1Delta mutant cells were compared with wild-type mitochondria with respect to the capability to take up Rf, to synthesize FAD from it, and to export FAD into the extramitochondrial phase. Mitochondria isolated from flx1Delta mutant cells specifically lost the ability to export FAD, but did not lose the ability to take up Rf, FAD, or FMN and to synthesize FAD from Rf. Hence, Flx1p is proposed to be the mitochondrial FAD export carrier. Moreover, deletion of the FLX1 gene resulted in a specific reduction of the activities of mitochondrial lipoamide dehydrogenase and succinate dehydrogenase, which are FAD-binding enzymes. For the flavoprotein subunit of succinate dehydrogenase we could demonstrate that this was not due to a changed level of mitochondrial FAD or to a change in the degree of flavinylation of the protein. Instead, the amount of the flavoprotein subunit of succinate dehydrogenase was strongly reduced, indicating an additional regulatory role for Flx1p in protein synthesis or degradation. 相似文献
87.
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. 相似文献
88.
Characterization and reconstitution of a 4Fe-4S adenylyl sulfate/phosphoadenylyl sulfate reductase from Bacillus subtilis 总被引:3,自引:0,他引:3
Berndt C Lillig CH Wollenberg M Bill E Mansilla MC de Mendoza D Seidler A Schwenn JD 《The Journal of biological chemistry》2004,279(9):7850-7855
CysH1 from Bacillus subtilis encodes a 3'-phospho/adenosine-phosphosulfate-sulfonucleotide reductase (SNR) of 27 kDa. Recombinant B. subtilis SNR is a homodimer, which is bispecific and reduces adenylylsulfate (APS) and 3'-phosphoadenylylsulfate (PAPS) alike with thioredoxin 1 or with glutaredoxin 1 as reductants. The enzyme has a higher affinity for PAPS (K(m)PAPS 6.4 microm Trx-saturating, 10.7 microm Grx-saturating) than for APS (K(m) APS 28.7 microm Trx-saturating, 105 microm Grx-saturating) at a V(max) ranging from 280 to 780 nmol sulfite mg(-1) min(-1). The catalytic efficiency with PAPS as substrate is higher by a factor of 10 (K(cat)/K(m) 2.7 x 10(4)-3.6 x 10(4) liter mol(-1) s(-1). B. subtilis SNR contains one 4Fe-4S cluster per polypeptide chain. SNR activity and color were lost rapidly upon exposure to air or upon dilution. M?ssbauer and absorption spectroscopy revealed that the enzyme contained a 4Fe-4S cluster when isolated, but degradation of the 4Fe-4S cluster produced an inactive intermediate with spectral properties of a 2Fe-2S cluster. Activity and spectral properties of the 4Fe-4S cluster were restored by preincubation of SNR with the iron-sulfur cluster-assembling proteins IscA1 and IscS. Reconstitution of the 4Fe-4S cluster of SNR did not affect the reductive capacity for PAPS or APS. The interconversion of the clusters is thought to serve as oxygen-sensitive switch that suppresses SO(3) formation under aerobiosis. 相似文献
89.
Polar localizing class V myosin chitin synthases are essential during early plant infection in the plant pathogenic fungus Ustilago maydis 下载免费PDF全文
Fungal chitin synthases (CHSs) form fibers of the cell wall and are crucial for substrate invasion and pathogenicity. Filamentous fungi contain up to 10 CHSs, which might reflect redundant functions or the complex biology of these fungi. Here, we investigate the complete repertoire of eight CHSs in the dimorphic plant pathogen Ustilago maydis. We demonstrate that all CHSs are expressed in yeast cells and hyphae. Green fluorescent protein (GFP) fusions to all CHSs localize to septa, whereas Chs5-GFP, Chs6-GFP, Chs7-yellow fluorescent protein (YFP), and Myosin chitin synthase1 (Mcs1)-YFP were found at growth regions of yeast-like cells and hyphae, indicating that they participate in tip growth. However, only the class IV CHS genes chs7 and chs5 are crucial for shaping yeast cells and hyphae ex planta. Although most CHS mutants were attenuated in plant pathogenicity, Deltachs6, Deltachs7, and Deltamcs1 mutants were drastically reduced in virulence. Deltamcs1 showed no morphological defects in hyphae, but Mcs1 became essential during invasion of the plant epidermis. Deltamcs1 hyphae entered the plant but immediately lost growth polarity and formed large aggregates of spherical cells. Our data show that the polar class IV CHSs are essential for morphogenesis ex planta, whereas the class V myosin-CHS is essential during plant infection. 相似文献
90.
Developmental mechanisms underlying tooth patterning in continuously replacing osteichthyan dentitions 总被引:1,自引:0,他引:1
Huysseune A Witten PE 《Journal of experimental zoology. Part B. Molecular and developmental evolution》2006,306(3):204-215
The dentition of osteichthyans presents an astonishing diversity with regard to the distribution of teeth in the oral cavity, tooth numbers, arrangements, shapes, and sizes. Taking examples from three unrelated teleosts--the most speciose group of osteichthyans--and from the literature, this study explores how the initial tooth pattern is set up, and how this relates to the establishment and maintenance (or modification) of the tooth replacement pattern. In teleosts, first-generation teeth (the very first teeth in ontogeny to develop at a particular locus) are commonly initiated in adjacent or in alternate (odd and even) positions. The mechanisms responsible for these divergent developmental patterns remain to be elucidated, in particular, whether they reflect a field or local type of control. However, patterns of adjacent or alternate tooth initiation, set up by the first-generation teeth, can easily turn into replacement patterns where new teeth are initiated simultaneously every second, or even every third position, by synchronizing the formation of new first-generation teeth to the formation of replacement teeth at older loci. Our observations suggest that, once established, the replacement pattern appears to be maintained, as a kind of "default" state. Variations and modifications in this pattern are nevertheless common and suggest that tooth replacement is under local control, exerted at the level of the initiation of replacement teeth. Further studies are needed to test the hypothesis that regular replacement patterns are more frequent in association with the plesiomorphic condition of extramedullary replacement (replacement on the surface of the dentigerous bone) and more rare in the derived condition of intramedullary replacement (replacement within the medullary cavity of the dentigerous bone). 相似文献