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Author: Catrina Ann Chitjian
Publisher:
ISBN:
Category :
Languages : en
Pages : 332
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Book Description
Eukaryotic elongation factor 2 kinase (eEF-2K) is a calmodulin (CaM)/calcium regulated kinase whose activity disrupts translation elongation resulting in the global decrease of protein synthesis1. Translation is one of the most energy intensive processes in a cell; eEF-2K is critical in maintaining cellular homeostasis. The dysregulation of eEF-2K is associated with an assortment of diseases including several types of cancer2, depression [superscript 3,4], and Alzheimer’s disease5, which has prompted closer examination across multiple studies of the enzyme in recent decades. Notably, the kinetic mechanism of eEF-2K has been detailed as a two-step process: 1) The binding of Ca2+-CaM enables the autophosphorylation of Thr-348 and 2) The resulting conformational change enables eEF-2K to bind and phosphorylate its substrate. We have uncovered many surprising layers of eEF-2K regulation in past years, from kinetic mechanism to upstream affecters to models of CaM binding. This study focuses on the role of pH in regulating eEF-2K. pH homeostasis is also vital for cellular function. Even a slight disruption between the intra- and extracellular pH ratio can affect an array of processes such as ATP synthesis, enzyme function, as well as the proliferation, migration, and invasion of tumor cells6. Acidosis is a common effect of high intensity exercise, diabetic ketoacidosis, ischemia, and solid tumors [superscript 7–9]. It has been demonstrated that eEF-2K activity is increased and protein translation decreased in cells under acidic conditions, suggesting the enzyme’s potential cytoprotective effects [superscript 10–12]. This work reports the following: 1) A novel mechanism where H+ instead of Ca2+ activates eEF-2K; 2) A novel mechanism where H+ can replace Ca2+ in promoting eEF-2K substrate phosphorylation; 3) H+ promotes the binding of CaM to eEF-2K in a Ca2+-independent manner; 4) There are five histidine residues on eEF-2K that may contribute to the stabilized activity of eEF-2K under acidic conditions.
Author: Catrina Ann Chitjian
Publisher:
ISBN:
Category :
Languages : en
Pages : 332
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Book Description
Eukaryotic elongation factor 2 kinase (eEF-2K) is a calmodulin (CaM)/calcium regulated kinase whose activity disrupts translation elongation resulting in the global decrease of protein synthesis1. Translation is one of the most energy intensive processes in a cell; eEF-2K is critical in maintaining cellular homeostasis. The dysregulation of eEF-2K is associated with an assortment of diseases including several types of cancer2, depression [superscript 3,4], and Alzheimer’s disease5, which has prompted closer examination across multiple studies of the enzyme in recent decades. Notably, the kinetic mechanism of eEF-2K has been detailed as a two-step process: 1) The binding of Ca2+-CaM enables the autophosphorylation of Thr-348 and 2) The resulting conformational change enables eEF-2K to bind and phosphorylate its substrate. We have uncovered many surprising layers of eEF-2K regulation in past years, from kinetic mechanism to upstream affecters to models of CaM binding. This study focuses on the role of pH in regulating eEF-2K. pH homeostasis is also vital for cellular function. Even a slight disruption between the intra- and extracellular pH ratio can affect an array of processes such as ATP synthesis, enzyme function, as well as the proliferation, migration, and invasion of tumor cells6. Acidosis is a common effect of high intensity exercise, diabetic ketoacidosis, ischemia, and solid tumors [superscript 7–9]. It has been demonstrated that eEF-2K activity is increased and protein translation decreased in cells under acidic conditions, suggesting the enzyme’s potential cytoprotective effects [superscript 10–12]. This work reports the following: 1) A novel mechanism where H+ instead of Ca2+ activates eEF-2K; 2) A novel mechanism where H+ can replace Ca2+ in promoting eEF-2K substrate phosphorylation; 3) H+ promotes the binding of CaM to eEF-2K in a Ca2+-independent manner; 4) There are five histidine residues on eEF-2K that may contribute to the stabilized activity of eEF-2K under acidic conditions.
Author: Clint Damian Jaxon Tavares
Publisher:
ISBN:
Category :
Languages : en
Pages : 528
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Book Description
Eukaryotic elongation factor 2 kinase (eEF-2K) is an atypical calcium/calmodulin-dependent protein kinase (CaMK-III). The kinase provides a mechanism by which cells can globally control the rate of the elongation phase of protein synthesis, through inhibition of its only known substrate, elongation factor 2 (eEF-2). eEF-2K has been reported to promote proliferation, migration and survival of cancer cells, and has also been implicated in depression. Understanding the regulation of kinase activity is important for development of inhibitors to treat these disease states. However, the mechanisms through which upstream kinases regulate eEF-2K activity via multisite phosphorylation, and how calcium and calmodulin contribute to this, are still unclear. This deficiency may result from the difficulty of obtaining the recombinant kinase in a form suitable for biochemical analysis. This work reports the purification (a three-step protocol using a calmodulin-affinity column) and characterization of recombinant human eEF-2K expressed in E. coli. Mass spectrometry identified Thr-348 and Ser-500 as major calcium/calmodulin-stimulated autophosphorylation sites. Rapid quench analysis indicates that the rate of Thr-348 autophosphorylation is extremely fast (k = 2.6 s−1, t [subscript 1⁄2] ~ 279 ms), and requires calmodulin. Mutagenesis studies suggest that phosphorylation at Thr-348 is required for eEF-2 phosphorylation both in vitro and in cells. However, while T348A has an overall lower activity than the WT kinase, the extent of stimulation of eEF-2K activity by 2-deoxy-D-glucose, hydrogen peroxide, ionomycin or cellular starvation is the same for both forms of the kinase. Thus, to control the amplitude of eEF-2K activity in cells following a stimulus that promotes calmodulin binding, phosphorylation at Thr-348 could act as an additional allosteric switch. This could potentially occur though interaction with a putative phosphate-binding pocket comprised of Lys-205, Arg-252 and Thr-254. Additionally, we observed that Ser-500 phosphorylation promotes an increase in affinity for calmodulin, and we provide evidence that Ser-500 phosphorylation on the eEF-2K•calmodulin complex significantly enhances the already rapid rate of Thr-348 autophosphorylation. Here we propose a two-step model involving calcium/calmodulin binding and Thr-348 autophosphorylation to modulate eEF-2K activity. Phosphorylation at Ser-500 is able to alter the kinetics at both these levels of regulation.
Author: David Harold Giles
Publisher:
ISBN:
Category :
Languages : en
Pages : 202
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Book Description
Translation of mRNA to protein is essential to all life, and is carried out by the ribosome with the assistance of various initiation and elongation factors. The rate and location at which translation occurs is subject to regulation by an intricate network of positive and negative signaling mechanisms. Such regulation allows the cell to respond to changes in external conditions, such as a sudden drop in nutrient availability. In higher eukaryotes, a key component of this regulation is the phosphorylation of elongation factor 2 (eEF-2) - the enzyme which catalyzes ribosome translocation along the mRNA - by eEF-2 kinase (eEF-2K) on Thr56. This event impedes the affinity of eEF-2 for the ribosome and therefore lowers the rate of protein synthesis. The activity of eEF-2K is tightly regulated by upstream signals, including Ca2+-calmodulin and post-translational modification. Aberrant regulation of the eEF-2K axis is known in various disease states, including cancer and depression, yet the molecular mechanisms by which eEF-2K processes the multiple signals that communicate with it are poorly defined. This gap in knowledge precludes the rational design of eEF-2Ktargeting treatments which may be effective at treating such diseases. Here, three broad topics are discussed. First, an overview of what is currently known about the structure, function, and regulation of eEF-2K is presented. Second, we elucidate the mechanisms by which eEF-2K integrates signals at the nutrient-sensitive signaling node. Finally, we characterize a highly active form of eEF-2K which provides insight into the potential structure-function relationship of key portions of the enzyme. Taken together, this work is an important step towards a complete description of the biochemical mechanisms by which eEF-2K is regulated by diverse inputs
Author: Kelly Hooper
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Linda J. Van Eldik
Publisher: Academic Press
ISBN: 0080926363
Category : Science
Languages : en
Pages : 497
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Book Description
Calmodulin and Signal Transduction focuses on emerging themes in the molecular mechanisms of calcium signal transduction through calmodulin-regulated pathways. It provides the reader with selected examples and experimental precedents that underlie current models of cell regulation through calmodulin-regulated pathways and their linkage with other regulatory pathways. - Molecular mechanisms of calcium signal transduction through calmodulin-regulated enzymes - Selected case studies and precedents related to molecular mechanisms - Protein-protein recognition between calmodulin and the enzymes it regulates - Cross-talk and interdigitation with other signal transduction pathways
Author: Tommaso Pizzorusso
Publisher: Frontiers Media SA
ISBN: 2889456579
Category : Neurosciences. Biological psychiatry. Neuropsychiatry
Languages : en
Pages : 346
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Book Description
Until about a decade ago, the non-coding part of the genome was considered without function. RNA sequencing studies have shown, however, that a considerable part of the non-coding genome is transcribed and that these non-coding RNAs (nc-RNAs) can regulate gene expression. Almost on weekly basis, new findings reveal the regulatory role of nc-RNAs exert in many biological processes. Overall, these studies are making increasingly clear that, both in model organisms and in humans, complexity is not a function of the number of protein-coding genes, but results from the possibility of using combinations of genetic programs and controlling their spatial and temporal regulation during development, senescence and in disease by regulatory RNAs. This has generated a novel picture of gene regulatory networks where regulatory nc-RNAs represent novel layers of regulation. Particularly well-characterized is the role of microRNAs (miRNAs), small nc-RNAs, that bind to mRNAs and regulate gene expression after transcritpion. This message is particularly clear in the nervous system, where miRNAs have been involved in regulating cellular pathways controlling fundamental functions during development, synaptic plasticity and in neurodegenerative disease. It has also been shown that neuronal miRNAs are tightly regulated by electrical activity at the level of transcription, biogenesis, stability and specifically targeted to dendrites and synapses. Deregulation of expression of miRNAs is proposed not only as potential disease biomarker, but it has been implicated directly in the pathogenesis of complex neurodegenerative disease. This so-called RNA revolution also lead to the exploitation of RNA interference and the development of related tools as potential treatment of a vast array of CNS disease that could benefit from regulation of disease-associated genes. In spite of these advancements, the relatively young age of this field together with the inherent high molecular complexity of RNA regulation of biological processes have somewhat hindered its communication to the whole of the neuroscience community. This Research Topic aims at improving this aspect by putting around the same virtual table scientists covering aspects ranging from basic molecular mechanisms of regulatory RNAs in the nervous system to the analysis of the role of specific regulatory RNAs in neurobiological processes of development, plasticity and aging. Furthermore, we included papers analyzing the role of regulatory RNAs in disease models from neuromuscular to higher cognitive functions, and more technically oriented papers dealing with new methodologies to study regulatory RNA biology and its translational potential.
Author: Sam Thiagalingam
Publisher: Cambridge University Press
ISBN: 0521493390
Category : Mathematics
Languages : en
Pages : 597
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Book Description
An overview of the current systems biology-based knowledge and the experimental approaches for deciphering the biological basis of cancer.
Author: Ralph A. Bradshaw
Publisher: Academic Press
ISBN: 0080920918
Category : Science
Languages : en
Pages : 3188
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Book Description
Handbook of Cell Signaling, Three-Volume Set, 2e, is a comprehensive work covering all aspects of intracellular signal processing, including extra/intracellular membrane receptors, signal transduction, gene expression/translation, and cellular/organotypic signal responses. The second edition is an up-to-date, expanded reference with each section edited by a recognized expert in the field. Tabular and well illustrated, the Handbook will serve as an in-depth reference for this complex and evolving field. Handbook of Cell Signaling, 2/e will appeal to a broad, cross-disciplinary audience interested in the structure, biochemistry, molecular biology and pathology of cellular effectors. - Contains over 350 chapters of comprehensive coverage on cell signaling - Includes discussion on topics from ligand/receptor interactions to organ/organism responses - Provides user-friendly, well-illustrated, reputable content by experts in the field
Author:
Publisher: Academic Press
ISBN: 0123786312
Category : Science
Languages : en
Pages : 3223
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Book Description
The 4-volume Encyclopedia of Biological Chemistry, Second Edition, represents the current state of a dynamic and crucial field of study. The Encyclopedia pulls together over 500 articles that help define and explore contemporary biochemistry, with content experts carefully chosen by the Editorial Board to assure both breadth and depth in its coverage. Editors-In-Chief William J. Lennarz and M. Daniel Lane have crafted a work that proceeds from the acknowledgement that understanding every living process-from physiology, to immunology, and genetics-is impossible without a grasp on the basic chemistry that provides its underpinning. Each article in the work provides an up-to-date snapshot of a given topic, written by experts, as well as suggestions for further readings for students and researcher wishing to go into greater depth. Available on-line via SciVerse ScienceDirect, the functionality of the Encyclopedia will provide easy linking to referenced articles, electronic searching, as well an online index and glossary to aid comprehension and searchability. This 4-volume set, thoroughly up-to-date and comprehensive, expertly captures this fast-moving field Curated by two esteemed editors-in-chief and an illustrious team of editors and contributors, representing the state of the field Suggestions for further readings offer researchers and students avenues for deeper exploration; a wide-ranging glossary aids comprehension
Author: Astrid Sigel
Publisher: Springer Science & Business Media
ISBN: 9400775008
Category : Science
Languages : en
Pages : 603
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Book Description
MILS-13 provides an up-to-date review on the relationships between essential metals and human diseases, covering 13 metals and 3 metalloids: The bulk metals sodium, potassium, magnesium, and calcium, plus the trace elements manganese, iron, cobalt, copper, zinc, molybdenum, and selenium, all of which are essential for life. Also covered are chromium, vanadium, nickel, silicon, and arsenic, which have been proposed as being essential for humans in the 2nd half of the last century. However, if at all, they are needed only in ultra-trace amounts, and because of their prevalence in the environment, it has been difficult to prove whether or not they are required. In any case, all these elements are toxic in higher concentrations and therefore, transport and cellular concentrations of at least the essential ones, are tightly controlled; hence, their homeostasis and role for life, including deficiency or overload, and their links to illnesses, including cancer and neurological disorders, are thoroughly discussed. Indeed, it is an old wisdom that metals are indispensable for life. Therefore, Volume 13 provides in an authoritative and timely manner in 16 stimulating chapters, written by 29 internationally recognized experts from 7 nations, and supported by more than 2750 references, and over 20 tables and 80 illustrations, many in color, a most up-to-date view on the vibrant research area of the Interrelations between Essential Metal Ions and Human Diseases.
