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Encyclopedia > Phosphorylation
A phosphorylated serine residue
A phosphorylated serine residue

Phosphorylation is the addition of a phosphate (PO4) group to a protein molecule or a small molecule. Another way to define it would be the introduction of a phosphate group into an organic molecule. Its prominent role in biochemistry is the subject of a very large body of research (as of January 2006, the Medline database returns over 120,000 articles on the subject, largely on protein phosphorylation). Image File history File links Phosphorylated_serine. ... Image File history File links Phosphorylated_serine. ... Serine (IPA ), organic compound, one of the 20 amino acids commonly found in animal proteins. ... A phosphate, in inorganic chemistry, is a salt of phosphoric acid. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Biochemistry is the study of the chemical processes in living organisms. ... It has been suggested that GoPubMed be merged into this article or section. ...

Contents

Protein phosphorylation

History

In 1906, Phoebus A. Levene at the Rockefeller Institute for Medical Research identified phosphate in the protein Vitellin (phosvitin),[1] and by 1933 had detected phosphoserine in Casein, with Fritz Lipmann.[2] However, it took another 20 years before Eugene P. Kennedy described the first ‘enzymatic phosphorylation of proteins’.[3]


Function

Reversible phosphorylation of proteins is an important regulatory mechanism which occurs in both prokaryotic and eukaryotic organisms.[4][5][6][7] Enzymes called kinases (phosphorylation) and phosphatases (dephosphorylation) are involved in this process. Many enzymes and receptors are switched "on" or "off" by phosphorylation and dephosphorylation. Reversible phosphorylation results in a conformational change in the structure in many enzymes and receptors, causing them to become activated or deactivated. Phosphorylation usually occurs on serine, threonine, and tyrosine residues in eukaryotic proteins. In addition to serine, threonine, and tyrosine residues phosphorylation occurs on the basic amino acid residues histidine or arginine or lysine in prokaryotic proteins[4][5]. The addition of a phosphate (PO4) molecule to a polar R group of an amino acid residue can turn a hydrophobic portion of a protein into a polar and extremely hydrophilic portion of molecule. In this way it can introduce a conformational change in the structure of the protein via interaction with other hydrophobic and hydrophilic residues in the protein. Prokaryotic bacteria cell structure Prokaryotes (IPA: //) are a group of organisms that lack a cell nucleus (= karyon), or any other membrane-bound organelles. ... Kingdoms Animalia - Animals Fungi Plantae - Plants Chromalveolata Protista Alternative phylogeny Unikonta Opisthokonta Metazoa Choanozoa Eumycota Amoebozoa Bikonta Apusozoa Cabozoa Rhizaria Excavata Corticata Archaeplastida Chromalveolata Animals, plants, fungi, and protists are eukaryotes (IPA: ), organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. ... A protein kinase is an enzyme that can transfer a phosphate group from a donor molecule (usually ATP) to an amino acid residue of a protein. ... A phosphatase is an enzyme that hydrolyses phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxy group. ... Neuraminidase ribbon diagram An enzyme (in Greek en = in and zyme = blend) is a protein, or protein complex, that catalyzes a chemical reaction and also controls the 3D orientation of the catalyzed substrates. ... Receptor may refer to: In telecommunication, a receiver. ... Proteins are an important class of biological macromolecules present in all biological organisms, made up of such elements as carbon, hydrogen, nitrogen, oxygen, and sulfur. ... Neuraminidase ribbon diagram An enzyme (in Greek en = in and zyme = blend) is a protein, or protein complex, that catalyzes a chemical reaction and also controls the 3D orientation of the catalyzed substrates. ... Receptor may refer to: In telecommunication, a receiver. ... Serine (IPA ), organic compound, one of the 20 amino acids commonly found in animal proteins. ... Threonine is one of the 20 natural amino acids. ... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese[1][2]), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells... Serine (IPA ), organic compound, one of the 20 amino acids commonly found in animal proteins. ... Threonine is one of the 20 natural amino acids. ... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese[1][2]), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells... Histidine is one of the 20 most common natural amino acids present in proteins. ... Arginine (abbreviated as Arg or R)[1] is an α-amino acid. ... Lysine is one of the 20 amino acids normally found in proteins. ...


One such example of the regulatory role that phosphorylation plays is the p53 tumor suppressor protein. The p53 protein is heavily regulated[8] and contains more than 18 different phosphorylation sites. Activation of p53 can lead to cell cycle arrest, which can be reversed under some circumstances, or apoptotic cell death[9] This activity only occurs in situations where the cell is damaged or physiology is disturbed in normal healthy individuals. Expression pattern Orthologs Human Mouse Entrez Ensembl Uniprot Refseq Location p53, also known as protein 53 (TP53), is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. ...


Upon the deactivating signal, the protein becomes dephosphorylated again and stops working. This is the mechanism in many forms of signal transduction, for example the way in which incoming light is processed in the light-sensitive cells of the retina. In biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another, most often involving ordered sequences of biochemical reactions inside the cell, that are carried out by enzymes and linked through second messengers resulting in what is thought of as... Human eye cross-sectional view. ...


Regulatory roles of phosphorylation include

  • Biological thermodynamics of energy-requiring reactions
    • Phosphorylation of Na+/K+-ATPase during the transport of sodium (Na+) and potassium(K+) ions across the cell membrane in osmoregulation to maintain homeostasis of the body's water content.
  • Mediates enzyme inhibition
    • phosphorylation of the enzyme GSK-3 by AKT (Protein kinase B) as part of the insulin signaling pathway.[10]
    • phosphorylation of src tyrosine kinase (pronounced "sarc") by C-terminal Src kinase (Csk) induces a conformational change in the enzyme resulting in a fold in the structure which masks its kinase domain, and is thus shut "off".[11]
  • Important for protein-protein interaction via "recognition domains".
    • Phosphorylation of the cytosolic components of NADPH oxidase a large membrane bound, multi-protein enzyme present in phagocytic cells plays an important role in the regulation of protein-protein interactions in the enzyme.[12]
  • Important in protein degradation.
    • In the late 1990s it was recognized that phosphorylation of some proteins causes them to be degraded by the ATP-dependent ubiquitin/proteasome pathway. These target proteins become substrates for particular E3 ubiquitin ligases only when they are phosphorylated.

This article is about the study of energy transformation in Biology and related subjects. ... Simplified Diagram of the sodium pump Na+/K+-ATPase (also known as the Na+/K+ pump or Na+/K+ exchanger) is an enzyme (EC 3. ... Osmoregulation is the active regulation of the osmotic pressure of bodily fluids to maintain the homeostasis of the bodys water content; that is it keeps the bodys fluids from becoming too dilute or too concentrated. ... Homeostasis is the property of either an open system or a closed system, especially a living organism, which regulates its internal environment so as to maintain a stable, constant condition. ... HIV protease in a complex with the protease inhibitor ritonavir. ... Glycogen Synthase Kinase 3 (GSK-3) is a serine/threonine protein kinase. ... Akt, also known as protein kinase B (PKB) is an important molecule in mammalian cellular signaling. ... Src is a family of proto-oncogenes that may lead to cancer. ... Protein-protein interactions refer to the association of protein molecules and the study of these associations from the perspective of biochemistry, signal transduction and networks. ... --RAG 01:54, 16 March 2007 (UTC) The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray crystallographic studies of hen lysozyme (Phillips, 1966), papain (Drenth et al. ... The NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) complex is an enzyme complex that is made up of five subunits. ... A phagocyte is a cell that ingests and destroys foreign matter such as microorganisms or debris via a process known as phagocytosis. ... Ubiquitin is a very conserved small regulatory protein that is ubiquitous in eukaryotes. ... A proteasome is a barrel-shaped multi-protein complex that can digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. ... Ubiquitin is a very conserved small regulatory protein that is ubiquitous in eukaryotes. ...

Signaling networks

Elucidating complex signalling pathway phosphorylation events can be difficult. In some cellular signalling pathways, a protein A phosphorylates B, and B phosphorylates C, but A also phosphorylates C directly, and B can phosphorylate D, which may in turn phosphorylate A. Global approaches such as phosphoproteomics the study of phosphorylated proteins which is a sub-branch of proteomics combined with mass spectrometry-based proteomics, have been utilised to identify and quantify dynamic changes in phosphorylated proteins over time. These techniques are becoming increasingly important for the systematic analysis of complex phosphorylation networks.[13] They have been sucessfully used to identify dynamic changes in the phosphorylation status of more than 6000 sites after stimulation with epidermal growth factor.[13][14] Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. ... Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. ... Phosphoproteomics is a branch of proteomics that identifies, catalogs, and characterizes proteins containing phosphate as a post-translational modification. ... For the journal Proteomics, see Proteomics (journal). ... Mass spectrometry (previously called mass spectroscopy (deprecated)[1] or informally, mass-spec and MS) is an analytical technique used to measure the mass-to-charge ratio of ions. ... For the journal Proteomics, see Proteomics (journal). ... Epidermal Growth Factor or EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds. ...


Protein phosphorylation sites

There are thousands of distinct phosphorylation sites in a given cell since: 1) There are thousands of different kinds of proteins in any particular cell (such as a lymphocyte). 2) It is estimated that 1/10th to 1/2 of proteins are phosphorylated (in some cellular state). 3) Phosphorylation often occurs on multiple distinct sites on a given protein. A scanning electron microscope (SEM) image of a single human lymphocyte. ...


Since phosphorylation of any site on a given protein can change the function or localization of that protein, understanding the "state" of a cell requires knowing the phosphorylation state of its proteins. For example, if amino acid Serine-473 ("S473") in the protein AKT is phosphorylated AKT is generally functionally active as a kinase. If not, it is an inactive kinase. Akt, also known as protein kinase B (PKB) is an important molecule in mammalian cellular signaling. ... Akt, also known as protein kinase B (PKB) is an important molecule in mammalian cellular signaling. ...


Types of phosphorylation

See also kinases for more details on the different types of phosphorylation In biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific target molecules (substrates); the process is termed phosphorylation. ...


Within a protein, phosphorylation can occur on several amino acids. Phosphorylation on serine is the most common, followed by threonine. Tyrosine phosphorylation is relatively rare. However, since tyrosine phosphorylated proteins are relatively easy to purify using antibodies, tyrosine phosphorylation sites are relatively well understood. Histidine and aspartate phosphorylation occurs in prokaryotes as part of two-component signalling. This article is about the class of chemicals. ... Serine (IPA ), organic compound, one of the 20 amino acids commonly found in animal proteins. ... Threonine is one of the 20 natural amino acids. ... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese[1][2]), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells... Wikipedia does not yet have an article with this exact name. ... Histidine is one of the 20 most common natural amino acids present in proteins. ... Aspartic acid, also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Prokaryotes are unicellular (in rare cases, multicellular) organisms without a nucleus. ...


Detection and characterization

Antibodies can be used as powerful tools to detect whether a protein is phosphorylated at a particular site. Antibiodies bind to and detect phosphorylation-induced conformational changes in the protein. Such antibodies are called phospho-specific antibodies; hundreds of such antibodies are now available. They are becoming critical reagents both for basic research and for clinical diagnosis. Wikipedia does not yet have an article with this exact name. ... Wikipedia does not yet have an article with this exact name. ...

Example of posttranslational modification detected on a 2D gel (spot boundaries delimited by analysis software, identification by mass spectrometry , P46462 is the protein ID in Expasy)
Example of posttranslational modification detected on a 2D gel (spot boundaries delimited by analysis software, identification by mass spectrometry , P46462 is the protein ID in Expasy)

PTM (Phospho-Tyrosine Modified) isoforms are easily detected on 2D gels. Indeed, phosphorylation replaces neutral hydroxyl groups on serines, threonines or tyrosines with negatively charged phosphates with pKs near 1.2 and 6.5. Thus, below pH 5.5, phosphates add a single negative charge, near pH 6.5 they add 1.5 negative charges and above pH 7.5 they add 2 negative charges. The relative amount of each isoform can also easily and rapidly be determined from staining intensity on 2D gels. Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Two-dimensional gel electrophoresis, commonly abbreviated as 2-DE or 2-D electrophoresis, is a form of gel electrophoresis commonly used to analyze proteins. ...


A detailed characterization of the sites of phosphorylation is very difficult and the quantitation of protein phosphorylation by mass spectrometry requires isotopic internal standard approaches (Gerber et al., 2003). A relative quantitation can be obtained with a variety of differential isotope labeling technologies (Gigy et al., 2002, Goshe et al., 2003).


Other kinds

ATP, the "high-energy" exchange medium in the cell, is synthesized in the mitochondrion by addition of a third phosphate group to ADP in a process referred to as oxidative phosphorylation. ATP is also synthesized by substrate-level phosphorylation during glycolysis. ATP is synthesized at the expense of solar energy by photophosphorylation in the chloroplasts of plant cells. Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... Electron micrograph of a mitochondrion showing its mitochondrial matrix and membranes In cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle that is found in most eukaryotic cells. ... Adenosine diphosphate, abbreviated ADP, is a nucleotide. ... The Electron Transport Chain. ... Substrate-level phosphorylation is a type of chemical reaction that results in the formation of adenosine triphosphate (ATP) by the direct transfer of a phosphate group to adenosine diphosphate (ADP) from a reactive intermediate. ... The word glycolysis is derived from Greek γλυκύς (sweet) and λύσις (letting loose). ... The production of ATP using the energy of sunlight is called photophosphorylation. ... Chloroplasts are organelles found in plant cells and eukaryotic algae that conduct photosynthesis. ...


Phosphorylation of sugars is often the first stage of their catabolism. It allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across their transporter. This article is about sugar as food and as an important and widely traded commodity. ... Anabolism is the aspect of metabolism that contributes to growth. ...


External links

  • Mammalian Phosphorylation Resource, which integrates information on available phospho-specific antibodies
  • deltaMasses detection and localization of phosphorylations after mass spectrometry
  • Functional analyses for site-specific phosphorylation of a target protein in cells (A Protocol)

References

  1. ^ P.A. Levene and C.L. Alsberg, The cleavage products of vitellin, J. Biol. Chem. 2 (1906), pp. 127–133.
  2. ^ F.A. Lipmann and P.A. Levene, Serinephosphoric acid obtained on hydrolysis of vitellinic acid, J. Biol. Chem. 98 (1932), pp. 109–114.
  3. ^ G. Burnett and E.P. Kennedy, The enzymatic phosphorylation of proteins, J. Biol. Chem. 211 (1954), pp. 969–980.
  4. ^ a b A.J. Cozzon (1988) Protein phosphorylation in prokaryotes Ann. Rev. Microbiol. 42:97-125
  5. ^ a b J.B. Stock, A.J. Ninfa and A.M. Stock (1989) Protein phosphorylation and regulation of adaptive responses in bacteria. Microbiol. Rev., p. 450-490
  6. ^ C. Chang and R.C. Stewart (1998) The Two-Component System. Plant Physiol. 117: 723-731
  7. ^ D. Barford, A.K. Das and MP. Egloff. (1998) The Structure and mechanism of protein phosphatases: Insights into Catalysis and Regulation Annu Rev Biophys Biomol Struct. Vol. 27: 133-164
  8. ^ M. Ashcroft, M.H.G. Kubbutat, and K.H. Vousden (1999). Regulation of p53 Function and Stability by Phosphorylation. Mol Cell Biol Mar;19(3):1751-8.
  9. ^ S. Bates, and K. H. Vousden. (1996). p53 in signalling checkpoint arrest or apoptosis. Curr. Opin. Genet. Dev. 6:1-7.
  10. ^ P.C. van Weeren, K.M. de Bruyn, A.M. de Vries-Smits, J. Van Lint, B.M. Burgering. (1998). "Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB. J Biol Chem 22;273(21):13150-6.
  11. ^ Cole, P.A., Shen, K., Qiao, Y., and Wang, D. (2003) Protein tyrosine kinases Src and Csk: A tail's tale, Curr. Opin. Chem., Biol. 7:580-585.
  12. ^ Babior, B.M., (1999). NADPH oxidase: an update. Blood 93, pp. 1464–1476
  13. ^ a b J.V. Olsen, B.Blagoev, F. Gnad, B. Macek, C. Kumar, P. Mortensen, and M. Mann. (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 3;127(3):635-48.
  14. ^ Y. Li-Rong , H.J. Issaq and T.D. Veenstra. (2007) Phosphoproteomics for the discovery of kinases as cancer biomarkers and drug targets. Proteomics Clin. Appl. 1, 1042–1057

  Results from FactBites:
 
Phosphorylation - Wikipedia, the free encyclopedia (404 words)
Phosphorylation is the addition of a phosphate (PO) group to a protein or a small molecule.
An example of the important role that phosphorylation plays is the p53 tumor suppressor gene, which—when active—stimulates transcription of genes that suppress the cell cycle, even to the extent that it undergoes apoptosis.
Phosphorylation of sugars is often the stage of their catabolism.
  More results at FactBites »

 
 

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