Protein Phosphorylation

9 Key excerpts on "Protein Phosphorylation"

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  eBook - PDF

  Cell Chemistry and Physiology: Part II

  • Edward Bittar(Author)
  • 1996(Publication Date)
  • Elsevier Science

    (Publisher)

  In eukaryotic cells, phosphoserine and phosphothreonine account for over 99% of all phospho-rylated amino acids, while phosphotyrosine represents less than 0.03%. Minute amounts of phosphate may be covalently linked to lysine, arginine, histidine, aspartic acid, glutamic acid, and cysteine. Regulation of cellular functions by reversible phosphorylation involves signal transduction and amplification. In many cases, signal transduction is mediated by protein kinases, which catalyze the phosphotransferase reactions, and phosphoprotein phosphatases, which catalyze the cleavage of phosphate residues from the proteins. The steady-state level of phosphoprotein is determined by the kinase-phosphatase equilibrium: ATP ^ ^^ADP protein phosphoprotein Signal transduction also involves activators and inhibitors of kinases and phos-phatases as well as other cellular regulators which modulate the signal pathway. Amplification of the cellular signal results from small molecule and protein interaction at various levels to form an integrated relay network. That distinct enzyme pathways exist for phosphorylation and dephosphorylation is an important feature of this dynamic scheme as it allows for greater range of control by separate modifiers and for greater amplification. Function of Protein Phosphorylation-Depbosptiorylation 125 Most kinases phosphorylate a limited number of proteins in vitro at a physiologi-cal rate. Some of the most common protein substrates are the kinases themselves, and the reaction of the kinase catalyzing its own phosphorylation, is referred to as autophosphorylation. This process may reflect the fact that the autophosphorylation sites, or sites with similar structure, are located in the regulatory domains of kinases and act as competitive inhibitors of the protein kinase catalytic domains.

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  Protein Tyrosine Phosphatases

  Structure, Signaling and Drug Discovery

  • Lalima G. Ahuja(Author)
  • 2018(Publication Date)
  • De Gruyter

    (Publisher)

  1 Tyrosine phosphorylation in cell signaling: Discovery and beyond

  1.1 Protein Phosphorylation

  Protein Phosphorylation serves as the currency of cellular signaling and allows for protein functional regulation and spatial control. It is shown to be a key biological process in both prokaryotes and eukaryotes [1 ,2 ,3 ,4 ], and forms the basis of signaling pathways as we understand today. Protein Phosphorylation is a covalent modification wherein a phosphate (PO4 3− ) group is chemically attached to certain residues in target proteins. The negative charge of the phosphate allows for an alteration in the conformation of the said protein, thus allowing for a modulation of its function. The protein’s conformation change depends on its structural context and directly affects its activation/in-activation, protein–protein interaction with other cognate partners and also its own recycling in the cell. Many cellular receptors, adaptors, enzymes, transcription factors, DNA-binding modules and also cytoskeletal proteins are regulated for their spatiotemporal responses using a simple phosphorylation–dephosphorylation switch. As much 30% of all proteins in cells are speculated to be phosphorylated at any given time [5 ], and alterations in these phosphorylation states of these proteins are being increasingly linked to diseases and pathophysiology [6 ].

  Protein Phosphorylation predominantly occurs on the serine (Ser), threonine (Thr) and tyrosine (Tyr) amino acid side chains of proteins that form acid-stable phosphomonoesters using their hydroxyl side chains (Figure 1.1 ). Histidine (His), arginine (Arg) and lysine (Lys) residues use their basic side chains to form acid-labile phosphoramidates. Acidic residues, namely, aspartate (Asp) and glutamate (Glu) make acyl-phosphates. Cysteine (Cys) residues are phosphorylated on their sulfhydryl side chains to form thiophosphates. Multisite Protein Phosphorylation on serine/threonine and tyrosine residues is a key feature of many eukaryotic signaling processes [7 ]. Histidine and aspartate phosphorylations are a hallmark of the two-component system and multicomponent signaling systems that connect extracellular stimuli of osmolarity and nutrients to gene regulation in both bacteria and plants [8 , 9 ]. Histidine phosphorylation is known to be crucial in mammalian gene regulation with specific relevance in cardiovascular physiology and heart diseases [10 , 11 ]. Phosphoproteome analysis of the mammalian heart mitochondria has identified histidine and cysteine phosphorylations on pyruvate dehydrogenase and sarcomeric mitochondrial creatine kinase [12 ]. Histidine and cysteine phosphorylation are also shown to be important for the regulation of phosphoenolpyruvate-dependent carbohydrate transport system in prokaryotes [13 ]. As the phosphoramidates of arginine and lysine are difficult to detect, their significance is presently understudied. These nitrogen phosphorylations have been detected in histone proteins [14

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  Protein Phosphorylation in Human Health

  • Cai Huang(Author)
  • 2012(Publication Date)
  • IntechOpen

    (Publisher)

  Section 4 Protein Kinases and Phosphatases in Cell Cycle Regulation Chapter 13 © 2012 Fraschini et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Protein Phosphorylation is an Important Tool to Change the Fate of Key Players in the Control of Cell Cycle Progression in Saccharomyces cerevisiae Roberta Fraschini, Erica Raspelli and Corinne Cassani Additional information is available at the end of the chapter http://dx.doi.org/10.5772/47809 1. Introduction Protein Phosphorylation is a reversible posttranslational modification that can modulate protein role in several physiological processes in almost every possible way. These include modification of its intrinsic biological activity, subcellular location, half-life and binding with other proteins. Protein Phosphorylation is particularly important for the regulation of key proteins involved in the control of cell cycle progression. Protein Phosphorylation is the covalent binding of a phosphate group to some critical residues of the polypeptide. The phosphorylation state of a protein is given by a balance between the activity of protein kinases and protein phosphatases. Eukaryotic protein kinases transfer phosphate groups (PO 4 3-) from ATP to an hydroxyl group of the lateral chain of specific serine, threonine or tyrosine residues on peptide substrates. In simple eukaryotic cells, like yeasts, Ser/Thr kinases are more common, while more complex eukaryotic cells, like human cells, have many Tyr kinases. Protein kinases recognize their substrates specifically and their active site consists of an activation loop and a catalytic loop between which substrates bind. Protein kinases differ from each other in the structure of their catalitic domain.

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  Protein Kinases

  • Gabriela Da Silva Xavier(Author)
  • 2012(Publication Date)
  • IntechOpen

    (Publisher)

  3 Alternating Phosphorylation with O-GlcNAc Modification: Another Way to Control Protein Function Victor V. Lima and Rita C. Tostes * Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto-SP, Brazil 1. Introduction As widely known, reversible phosphorylation of proteins, or the addition of a phosphate (PO4 3-) molecule to a polar R group of an amino acid residue, is an important regulatory mechanism that switches many enzymes and receptors on or off and therefore controls a range of cellular functions. Regulatory roles of phosphorylation include biological thermodynamics of energy-requiring reactions, enzyme and receptors’ activation or inhibition, protein-protein interaction via recognition domains, protein degradation. Kinases and phosphatases are involved in this process and these enzymes induce phosphorylation and dephosphorylation, respectively, of target proteins. Phosphorylation usually occurs on serine, threonine, and tyrosine ( O -linked), or histidine ( N -linked) residues of proteins, although arginine and lysine residues can also be phosphorylated. O -GlcNAcylation, or glycosylation with O -linked β -N-acetylglucosamine, is similar to Protein Phosphorylation in that both modifications occur on serine and threonine residues, both are dynamically added and removed in response to cellular signals, and both alter the function and associations of the modified protein. O -GlcNAcylation also modulates many cellular functions by mechanisms that include protein targeting to specific substrates, transient complex formation with other proteins, subcellular compartmentalization upon glycosylation of specific proteins and a complex interplay with protein O -phosphorylation, the main topic of this chapter.

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  Cell Signaling

  • Wendell A. Lim, Wendell Lim, Bruce Mayer, Tony Pawson(Authors)
  • 2014(Publication Date)
  • Garland Science

    (Publisher)

  Chapter 3 , we discussed some of the properties of the phosphate group that make it particularly useful for signaling: in short, phosphorylation allows the cell to use a readily available raw material (ATP) to induce stable and significant alterations in protein structure and function. Although the phosphoester linkage is relatively stable to spontaneous hydrolysis, in the cell its reactions can be rapidly catalyzed through the opposing actions of protein phosphatases and protein kinases.

  The importance of phosphorylation in regulating signaling pathways is suggested by the increasing importance of kinase inhibitors in the treatment of human disease. Since all protein kinases use ATP as a substrate of the phosphoryl transfer reaction, ATP analogs (small molecules that mimic ATP, but cannot be used for phosphate transfer) are useful as protein kinase inhibitors. Many of these compounds are now used clinically as drugs, for example, to inhibit kinases that cause cancer.

  Phosphorylation is often coupled with protein interactions

  In addition to its direct effects on protein structure, phosphorylation has another important role in signaling: it can dramatically affect the interaction of a protein with other proteins in the cell. As already noted, both serine/threonine and tyrosine phosphorylation lie at the heart of writer/eraser/reader systems, in which proteins containing modular phosphorylation-specific binding domains “read” changes in phosphorylation by binding specifically to certain proteins only after they are phosphorylated.

  This type of system was first appreciated in signaling by receptors with tyrosine kinase activity. When cells were stimulated with ligands for such receptors, in many cases the most abundantly phosphorylated substrate was found to be the receptor itself. This rather puzzling observation raised the question of how the signal was transmitted, in the absence of significant phosphorylation of downstream substrates. The discovery of a modular domain that binds specifically to peptides in the tyrosine- phosphorylated state (the SH2 domain) provided a solution to the puzzle: autophosphorylation of the receptor led to the recruitment of SH2- containing proteins from the cytosol to the receptor on the membrane. This change in localization brought SH2-containing enzymes into close proximity with their substrates on the membrane, thereby increasing their activity (Figure 4.11a

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  Cellular signaling and phosphoproteomics

  • Aleksei Anatoliyovych Stepanenko(Author)
  • 2019(Publication Date)
  • Delve Publishing

    (Publisher)

  ROLE OF Protein Phosphorylation IN THE REGULATION OF CELL CYCLE AND DNA-RELATED PROCESSES IN BACTERIA Citation Garcia-Garcia T, Poncet S, Derouiche A, Shi L, Mijakovic I, Noirot-Gros MF. Role of Protein Phosphorylation in the Regulation of Cell Cycle and DNA-Related Pro-cesses in Bacteria. Front Microbiol. 2016 Feb 16;7:184. doi: 10.3389/fmicb.2016.00184. eCollection 2016. Copyright © 2016 Garcia-Garcia, Poncet, Derouiche, Shi, Mijakovic and Noirot-Gros. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. CHAPTER 5 Transito Garcia-Garcia 1 , Sandrine Poncet 1 , Abderahmane Derouiche, 2 Lei Shi, 2 Ivan Mijakovic, 2,3 andMarie-Françoise Noirot-Gros 1, 1 Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France 2 Systems and Synthetic Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden 3 Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark Cellular Signaling and Phosphoproteomics 138 ABSTRACT In all living organisms, the phosphorylation of proteins modulates various aspects of their functionalities. In eukaryotes, Protein Phosphorylation plays a key role in cell signaling, gene expression, and differentiation. Protein Phosphorylation is also involved in the global control of DNA replication during the cell cycle, as well as in the mechanisms that cope with stress-induced replication blocks.

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  Signal Transduction

  • Bastien D. Gomperts, ljsbrand M. Kramer, Peter E.R. Tatham(Authors)
  • 2002(Publication Date)
  • Academic Press

    (Publisher)

  ..... Prote n dephosphorylation and | prote n phosphorylation II The importance of dephosphorylation The phosphorylation of proteins, at serine, threonine or tyrosine residues, serves multiple roles in the regulation of cell function. However, this is only half the story. If the transfer of phosphate groups to proteins is to serve as a precise and sensitive signalling mechanism, then necessarily it must operate against a low background. Dephosphorylation is thus as important as phosphorylation, and it follows that the phosphoprotein phosphatases are integral components of the signalling systems operated by protein kinases. 1 In a number of cases dephosphorylation serves as a true reset button, bringing proteins back to their resting state. A good example is the role of the serine/threonine phosphatase PP1G which dephosphorylates phosphorylase a, thereby terminating the breakdown of glycogen. There are other proteins (for example, glycogen synthase, Src, c-Jun, p56 Lck, NF-AT) that are phosphorylated under 'resting' conditions and then become active as a consequence of dephosphorylation (Figure 17.1). In particular, the transcription factor c-Jun requires both dephos- phorylation of serine/threonine residues near the DNA binding site, and phosphorylation of serines at the N-terminal region in order to be fully active. II Protein tyrosine phosphatases A soluble protein phosphatase specific for phosphotyrosines (PTP1B) was first isolated from human placenta. 2 Its amino acid sequence has stretches homologous with the tandem repeat domains present in the cytoplasmic portion of the leukocyte common antigen CD45. 3 This is a receptor-like protein expressed on the surface of cells of haematopoietic lineage. Using the DNA sequence that codes for the catalytic domain as a probe (the conserved 'signature motif' [I/V]HCXAGXXR[S/T]), many more protein tyrosine phosphatases were revealed.

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  The Roots of Modern Biochemistry

  Fritz Lippmann's Squiggle and its Consequences

  • Horst Kleinkauf, Hans von Döhren, Lothar Jaenicke, Horst Kleinkauf, Hans von Döhren, Lothar Jaenicke(Authors)
  • 2011(Publication Date)
  • De Gruyter

    (Publisher)

  The reaction catalyzed by the PK is reversible but not all serine (or tyrosine) phosphate groups in proteins are created equal - many are not high energy. Secondly, there is cooperativity in phosphorylations for the protein kinase they described. Some preexisting serine phosphate groups in the protein are required for further phosphorylation catalysis. I shall return to these observations later. During the interval of 23 years between the two papers emerging from Lipmann's laboratory, protein kinases and their regulatory functions have become very fashionable. Many reviews and books have been dedicated to this subjekt (cf. 4). In 1983, during a dinner with Lipmann, our conversation centered partly on an art show of recently exhibited water colors by Turner whom he greatly admired, but mostly on the role of tyrosine phosphorylation catalyzed by protein kinases of some oncogenes and on the importance of phosphorylation-dephosphorylation reactions in cancer and in life in general. This is the subject of my article and is dedicated to Fritz Lipmann, a hero in my own scientific life. 296 Efraim Racker General Comments Glycogen Phosphorylase was the first enzyme shown to be influenced by a phosphorylation-dephosphorylation process (5), Phosphorylase kinase the second (6), and glycogen synthase the third (7). The role of several protein kinase cascades was established and their complexities appreciated (8). Although earlier work suggested that protein kinases are specific, it is now clear that most protein kinases are promiscuous, and so are most substrates. Moreover, we now know that not every protein phosphorylated in vitro is necessarily phosphorylated in vivo. Not every protein that is phosphorylated in vivo needs to be of biological importance (Lesson 1). Lesson 1 Not everything that glitters is gold. Not every protein phosphorylated at a tyrosine residue deserves a grant.

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  Protein Phosphorylation

  • Friedrich Marks(Author)
  • 2008(Publication Date)
  • Wiley-VCH

    (Publisher)

  Protein Phosphorylation Edited by Friedrich Marks Weinheim - New York - Base1 - Cambridge - Tokyo This Page Intentionally Left Blank Protein Phosphorylation Edited by F. Marks 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim (Federal Republic of Germany), 1996 Distribution: VCH, P. 0. Box 10 11 61, D-69451 Weinheim (Federal Republic of Germany) Switzerland: VCH, P. 0. Box, CH-4020 Basel (Switzerland) United Kingdom and Ireland: VCH (UK) Ltd., 8 Wellington Court, Cambridge CB1 1HZ (England) USA and Canada: VCH, 220 East 23rd Street, New York, NY 10010-4606 (USA) Japan: VCH, Eikow Building, 10-9 Hongo 1-chome, Bunkyo-ku, Tokyo 113 (Japan) ISBN 3-527-29241-1 Protein Phosphorylation Edited by Friedrich Marks Weinheim - New York - Base1 - Cambridge - Tokyo Prof. Dr. Friedrich Marks Deutsches Krebsforschungszentrum Forschungsschwerpunkt I1 : Tumorzellregulation Abteilung : Biochemie gewebsspezifischer Regulation Im Neuenheimer Feld 280 D-69120 Heidelberg This book was carefully produced. Nevertheless, authors, editor and publisher do not warrant the infor- mation contained therein to be free of erros. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Published jointly by VCH Verlagsgesellschaft mbH, Weinheim (Federal Republic of Germany) VCH Publishers, Inc., New York, NY (USA) Editorial Director: Dr. Michael Bar Production Manager: Dip1.-Wirt.-Ing. (FH) Bernd Riedel Library of Congress Card No. applied for. * A catalogue record for this book is available from the British Library. Deutsche Bibliothek Cataloguing-in-Publication Data : Protein phosporylation I ed. by Friedrich Marks. - Weinheim ; New York ; Basel ; Cambridge ; Tokyo : VCH, 1996 NE: Marks, Friedrich [Hrsg.] 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim (Federal Republic of Germany), 1996 Printed on acid-free and chlorine-free paper. All rights reserved (including those of translation into other languages).

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