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 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

General principles of structure and function of the ribosome are surveyed, and the translating ribosome is regarded as a molecular conveying machine. Two coupled conveying processes, the passing of compact tRNA globules and the drawing of linear mRNA chain through intraribosomal channel, are considered driven by discrete acts of translocation during translation. Instead of mechanical transmission mechanisms and power-stroke 'motors', thermal motion and chemically induced changes in affinities of ribosomal binding sites for their ligands (tRNAs, mRNA, elongation factors) are proposed to underlie all the directional movements within the ribosomal complex. The GTP-dependent catalysis of conformational transitions by elongation factors during translation is also discussed.
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PMID:Ribosome as a molecular machine. 1190 72

Metabotropic glutamate receptors (mGlu) are GTP-binding (G) protein-coupled receptors (GPCRs) that are involved in learning and memory, cardiovascular control and motor function. Their structure and pharmacology has been reviewed recently in Current Drug Targets: CNS and Neurological Disorders (Vol. 1, Issue 3) where their roles in a variety of neurological disorders were highlighted. The present review focuses on the emerging evidence for interactions of mGlu receptors with other GPCRs in the CNS at the membrane interface and amongst signaling cascades in the cytosol (e.g. intracellular Ca(2+), cAMP and scaffolding proteins). While initially non-selective activity was thought to be responsible for many atypical responses, increasing evidence points to GPCR interactions in neurons and glia, with adrenoceptors, adenosine receptors, dopamine receptors and muscarinic receptors. For example, group II mGlu receptors were found to be required for group I mGlu receptor induction of long-term potentiation at the postsynaptic terminal. Increasing evidence demonstrates the intimate interaction of adenosine receptors and mGlu receptors, particularly in the regulation of neurotransmitter release. While adenosine itself can be released from astrocytes by co-activation of group II mGlu and beta-adrenergic receptors. Given the complexity of neurological disorders such as ischemic stroke, Alzheimer's disease and epilepsy, exploitation mGlu receptor-associated GPCR interactions may prove efficacious in the treatment of such disorders.
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PMID:Emerging signalling and protein interactions mediated via metabotropic glutamate receptors. 1276 3

The central features of the mechanical cycle that drives the contraction of muscle are two translational steps: the working stroke, whereby an attached myosin crossbridge moves relative to the actin filament, and the repriming step, in which the crossbridge returns to its original orientation. Although the mechanism of the first of these is understood in some detail, that of the second has received less attention. Here, we show that repriming occurs after detachment of the crossbridge from the actin, rather than intervening between two actomyosin states with ATP bound [Eisenberg, E. & Greene, L. E. (1980) Annu. Rev. Physiol. 42, 293-309]. To discriminate between these two models we investigated the single-molecule mechanics of the myosin-actin interaction in the presence of ATP analogues such as GTP, for which the hydrolytic step itself limits the actomyosin GTPase rate to a much lower rate than for ATP. The lifetimes of bound states was proportional to 1/[GTP], indicating that during the bound period myosin was in the actomyosin rigor configuration. Moreover, despite the very low actomyosin GTPase, the rate of actin binding and formation of the rigor state was higher than with ATP; it follows that most interactions with actin result in the release of GTP and not of the products, GDP and phosphate. There was no significant movement of the actin during this interaction, so repriming must occur while myosin is dissociated, as in the original Lymn-Taylor scheme [Lymn, R. W. & Taylor, E. W. (1971) Biochemistry 10, 4617-4624].
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PMID:Repriming the actomyosin crossbridge cycle. 1532 85

Chromosome movement during mitosis is powered in part by energy released through the depolymerization of kinetochore microtubules (MTs). Strong but indirect evidence suggests the existence of a specialized coupling between kinetochores and MT plus ends that enables this transduction of chemical energy into mechanical work. Analysis of this phenomenon is important for learning how energy is stored within the MT lattice, how it is transduced, and how efficient the process can be, given coupling devices of different designs. Here we use a recently developed molecular-mechanical model of MTs to examine the mechanism of disassembly dependent force generation. Our approach is based on changes in tubulin dimer conformation that occur during MT disassembly. We find that all of the energy of polymerization-associated GTP hydrolysis can be stored as deformations of the longitudinal bonds between tubulin dimers, and its optimal use does not require the weakening of lateral bonds between dimers. Maximum utilization of this stored energy and, hence, the generation of the strongest possible force, is achieved by a protofilament power-stroke mechanism, so long as the coupling device does not restrict full dissociation of the lateral bonds between tubulin dimers.
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PMID:Force production by depolymerizing microtubules: a theoretical study. 1576 80

Type I signal-anchor sequences mediate translocation of the N-terminal domain (N-domain) across the endoplasmic reticulum (ER) membrane. To examine the translocation in detail, dihydrofolate reductase (DHFR) was fused to the N-terminus of synaptotagmin II as a long N-domain. Translocation was arrested by the DHFR ligand methotrexate, which stabilizes the folding of the DHFR domain, and resumed after depletion of methotrexate. The targeting of the ribosome-nascent chain complex to the ER requires GTP, whereas N-domain translocation does not require any nucleotide triphosphates. Significant translocation was observed even in the absence of a lumenal hsp70 (BiP). When the nascent polypeptide was released from the ribosomes after the membrane targeting, the N-domain translocation was suppressed and the nascent chain was released from the translocon. Ribosomes have a crucial role in maintaining the translocation-intermediate state. The translocation of the DHFR domain was greatly impaired when it was separated from the signal-anchor sequence. Unfolding and translocation of the DHFR domain must be driven by the stroke of the signal-anchor sequence into translocon.
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PMID:Translocation of a long amino-terminal domain through ER membrane by following signal-anchor sequence. 1610 79

Axons fail to regenerate in the adult central nervous system (CNS) following injury. Developing strategies to promote axonal regeneration is therapeutically attractive for various CNS pathologies such as traumatic brain injury, stroke and Alzheimer's disease. Because the RhoA pathway is involved in neurite outgrowth, Rho-associated kinases (ROCKs), downstream effectors of GTP-bound Rho, are potentially important targets for axonal repair strategies in CNS injuries. We investigated the effects and downstream mechanisms of ROCK inhibition in promoting neurite outgrowth in a PC-12 cell model. Robust neurite outgrowth (NOG) was induced by ROCK inhibitors Y-27632 and H-1152 in a time-and dose-dependent manner. Dramatic cytoskeletal reorganization was noticed upon ROCK inhibition. NOG initiated within 5 to 30 minutes followed by neurite extension between 6 and 10 hours. Neurite processes were then sustained for over 24 hours. Rapid cofilin dephosphorylation was observed within 5 minutes of Y-27632 and H-1152 treatment. Re-phosphorylation was observed by 6 hours after Y-27632 treatment, while H-1152 treatment produced sustained cofilin dephosphorylation for over 24 hours. The results suggest that ROCK-mediated dephosphorylation of cofilin plays a role in the initiation of NOG in PC-12 cells.
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PMID:Direct Rho-associated kinase inhibition [correction of inhibiton] induces cofilin dephosphorylation and neurite outgrowth in PC-12 cells. 1684 45

The discovery that a myoglobin-like hemeprotein (called neuroglobin) is expressed in our brain raised considerable curiosity from the standpoints of biochemistry and pathophysiology alike. Neuroglobin is involved in neuroprotection from damage due to hypoxia or ischemia in vitro and in vivo; overexpression of neuroglobin ameliorates the recovery from stroke in experimental animals. The mechanism underlying this remarkable effect is still mysterious. Structural studies revealed that neuroglobin has a typical globin fold, and despite being hexacoordinated, it binds reversibly O2, CO, and NO, undergoing a substantial conformational change of the heme and of the protein. The possible mechanisms involved in neuroprotection are briefly reviewed. Neuroglobin is unlikely to be involved in O2 transport (like myoglobin), although it seems to act as a sensor of the O2/NO ratio in the cell, possibly regulating the GDP/GTP exchange rate forming a specific complex with the G(alpha beta gamma)-protein when oxidized but not when bound to a gaseous ligand. Thus it appears that neuroglobin is a stress-responsive sensor for signal transduction in the brain, mediated by a ligand-linked conformational change of the protein.
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PMID:A globin for the brain. 1707 95

Hemolysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemolysis and its effects on nitric oxide (NO) biology and further examination of the subphenotypes of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemolysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasodilatation. When plasma hemoglobin liberated from intravascularly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodilation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be linked to the intensity of hemolysis. Hemolysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemolytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials.
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PMID:Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. 1708 51

Vascular endothelial growth factor (VEGF) signaling is critical for both normal and disease-associated vascular development. Dysregulated VEGF signaling has been implicated in ischemic stroke, tumor angiogenesis, and many other vascular diseases. VEGF signals through several effectors, including the Rho family of small GTPases. As a member of this family, Rac1 promotes VEGF-induced endothelial cell migration by stimulating the formation of lamellipodia and membrane ruffles. To form these membrane protrusions, Rac1 is activated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP. The goal of this study was to identify the GEF responsible for activating Rac1 in response to VEGF stimulation. We have found that VEGF stimulates biphasic activation of Rac1 and for these studies we focused on the peak of activation that occurs at 30 min. Inhibition of VEGFR-2 signaling blocks VEGF-induced Rac1 activation. Using a Rac1 nucleotide-free mutant (G15ARac1), which has a high affinity for binding activated GEFs, we show that the Rac GEF Vav2 associates with G15ARac1 after VEGF stimulation. Additionally, we show that depleting endothelial cells of endogenous Vav2 with siRNA prevents VEGF-induced Rac1 activation. Moreover, Vav2 is tyrosine phosphorylated upon VEGF treatment, which temporally correlates with Rac1 activation and requires VEGFR-2 signaling and Src kinase activity. Finally, we show that depressing Vav2 expression by siRNA impairs VEGF-induced endothelial cell migration. Taken together, our results provide evidence that Vav2 acts downstream of VEGF to activate Rac1.
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PMID:VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2. 1768 71

ATP and other purine nucleotides are important biomarkers for ischemia and may have considerable potential as targets for management of ischemic heart disease and stroke. The main objective of the study is to develop a rapid HPLC assay, which has adequate sensitivity and specificity for measuring concentrations of ATP, ADP, AMP, GTP, GDP and GMP in erythrocytes (RBC). The assays used ion-pair chromatography coupled with ultraviolet detection at 254 nm to separate and detect the purine nucleotides. Using 50-100 microL of RBC lysate as blank biologic matrix, the assay was linear from 100 to 2000 microg/mL for ATP and ADP, and 20-400 microg/mL for AMP, GTP, and GDP with coefficients of determination (r(2)) >0.99. GDP and GMP were not measurable in the study because of low concentrations and interference from endogenous materials, respectively. The intra-assay and inter-assay variations over a period of 1 year were less than 10% and 20%, respectively for most of the nucleotides. The assay was successfully applied to two pilot biomarker studies to measure RBC concentrations of the purine nucleotides in rats under restraining and exercise conditions. Preliminary results showed that the RBC concentrations of ATP and GTP were higher in the spontaneously hypertensive rats (SHR) compared to the Sprague-Dawley (SD) rats, and that exercise increased RBC concentrations of ATP in rats treated with the calcium channel blocker diltiazem.
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PMID:HPLC assay with UV detection for determination of RBC purine nucleotide concentrations and application for biomarker study in vivo. 1829 98


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