Phosphorylation of serine

Phosphorylation is a common method of regulation. As described above, SH2 domains bind to phosphorylated tyrosine residues. Conversely, phosphorylation of serines and threonines proximal to SH3 and PDZ domains uncouples them from their target motifs. Therefore modulation of protein kinase activity in cells regulates interactions between adaptor proteins and their target proteins. 

Given that these proteins have properly assembled, the initiation complex is ready to start transcription. How does the enzyme get started A component of TFIID, again a multi-subunit complex TFIIH, unwinds the DNA and phosphorylates serine-5 of the C-terminal tail (CTD) of the largest polymerase subunit (Rpbl). Serine-5 phosphorylation and phosphorylation of serine-2 (by pTEFb) are required to release the enzyme from the other components of the initiation complex and to start RNA synthesis. 

Although in in vivo circumstances an intracellular free calcium increase apparently acts as the primary modulator of contraction, it can be bypassed in highly permeabilized smooth muscle preparations where the active subunit of MLCK can be introduced to phosphorylate myosin and induce contraction. The MLCK catalyzed phosphorylation of serine-19 is seen as the necessary event in the activation of smooth muscle myosin to form crossbridges. Thus, the rising phase of force during an isometric smooth muscle contraction follows an increase in the degree of phosphorylation of myosin, and that in turn follows the transient rise of (a) cytosolic free Ca, (b) Ca-calmodulin complexes, and (c) the active form of MLCK. The regulation of the intracellular calcium is discussed below. The dynam-... 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

Ramsey A., Fitzpatrick P. (1998). Effects of phosphorylation of serine 40 of tyrosine hydroxylase on binding of catecholamines evidence for a novel regulatory mechanism. Biochemistry 37, 8980-6. 

Activation of cells results in the release of IKB, followed by the rapid proteolysis of IKB. Although phosphorylation of serine 32 and 36 in the amino-terminal part of IKBa occurs when the proinflammatory cytokines or mitogens are administered to a T lymphocytic cell line, a different site of action has been found after H2O2 incubation (Schoonbroodt et al., 2000). The tyrosine residue 42 and the C-terminal PEST (Pro-Glu-Ser-Thr) domain plays a major role in the phosphorlylation of IKB after treatment with H2O2. Furthermore the CVinducible phosphorylation was not dependent upon IKB kinase activation but involved casein kinase II. The importance of iron for the activation of NFKB was underlined by the fact that... 

A major way to control enzyme activity is the reversible phosphorylation of serine or threonine residues. It s such a major way to regulate enzymes that you will spend much of your time trying to remember whether or not enzyme X is activated or inactivated by phosphorylation, and you will invariably forget one or two of them on the exam. By remembering a couple of generalities,2 you can actually figure out a lot of the effects of phosphorylation on specific enzymes without really memorizing them. 

FIGURE 1 2-2 Schematic diagram of the phosphorylation sites on each of the four 60kDa subunits of tyrosine hydroxylase (TOHase). Serine residues at the N-terminus of each of the four subunits of TOHase can be phosphorylated by at least five protein kinases. (J), Calcium/calmodulin-dependent protein kinase II (CaM KII) phosphorylates serine residue 19 and to a lesser extent serine 40. (2), cAMP-dependent protein kinase (PKA) phosphorylates serine residue 40. (3), Calcium/phosphatidylserine-activated protein kinase (PKC) phosphorylates serine 40. (4), Extracellular receptor-activated protein kinase (ERK) phosphorylates serine 31. (5), A cdc-like protein kinase phosphorylates serine 8. Phosphorylation on either serine 19 or 40 increases the activity of TOHase. Serine 19 phosphorylation requires the presence of an activator protein , also known as 14-3-3 protein, for the expression of increased activity. Phosphorylation of serines 8 and 31 has little effect on catalytic activity. The model shown includes the activation of ERK by an ERK kinase. The ERK kinase is activated by phosphorylation by PKC. (With permission from reference [72].)... 

CREB is also phosphorylated on serine 133 by stimulation of growth factor signaling cascades [63]. This occurs via a complex pathway involving MAPK cascades (Fig. 23-9). Thus, as outlined earlier, nerve growth factor and related neurotrophins that act on receptor tyrosine kinases lead to the successive activation of Ras, Raf, MEK and ERK. Activated ERK then phosphorylates and activates a serine-threonine kinase, RSK, particular subtypes of which directly activate CREB via the phosphorylation of serine 133. 

The covalent modification of cellular proteins by phosphorylation of serine/ threonine and tyrosine residues provides an efficient molecular switch for altering cellular responses. 

Phosphorylation of serine, threonine, or tyrosine residues by protein kinases, and their dephosphorylation by protein phosphatases, are critical mechanisms by which information-relaying signals are transduced in eukaryotic cells. Although protein kinases are by no means an eukaryotic invention (see Leonard et al., 1998 for details), the large numbers of protein kinases in eukaryotes (118 in. S . cerevisiae and 435 in C. elegans (Chervitz et al., 1998)) reflect their importance in a multitude of diverse cellular processes. Eukaryotes have evolved signaling pathways that exploit the dual state of an amino acid, dependent on its state of phosphorylation, both as a signaling mechanism and as a means of colocalization of molecules within multimolecular complexes. 

Lo WS, Trievel RC, Rojas JR, Duggan L, Hsu JY, Allis CD, Marmorstein R, Berger SL (2000) Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol Cell 5(6) 917—926... 

Maile T, Kwoczynski S, Katzenberger RJ, Wassarman DA, Sauer E (2004) TAEl activates transcription by phosphorylation of serine 33 in histone H2B. Science 304(5673) 1010-1014... 

Polioudaki H, Markaki Y, Kourmouli N, Dialynas G, Theodoropoulos PA, Singh PB, Georgatos SD (2004) Mitotic phosphorylation of histone H3 at threonine 3. FEBS Lett 560(l-3) 39 4 Preuss U, Landsberg G, Scheidtmann KH (2003) Novel mitosis-specific phosphorylation of histone H3 at Thrll mediated by Dlk/ZIP kinase. Nucleic Acids Res 31(3) 878-885 Prigent C, Dimitrov S (2003) Phosphorylation of serine 10 in histone H3, what for J Cell Sci 116(Pt 18) 3677-3685... 

A high proportion of the positiveiy charged basic amino acids lysine and arginine within these flexible tails are frequent targets for extensive posttranslational modifications (Berger, 2002). Such modifications include the acetylation of lysine residues, the methylation of lysine and arginine residues, the ubiquitination of lysine residues, the phosphorylation of serine and threonine residues, the sumoylation of lysine residues, and the poly ADP-ribosylation of glutamic acid residues. 

In case of the P -adrenergic receptor, phosphorylation of serine and threonine residues in the carboxyl tail can be shown to be involved in desensitization and internalization (141,156). Other GPCRs—such as the p- and 5-opioid receptors... 

A true appreciation of the subtle and complex ways in which the nucleosome can influence gene expression, has come only recently, largely through studies of the post-translational modifications to which all histones are subject and of the enzymes that add and remove these modifications. It has been known for many years that the histone N-terminal tails are exposed on the surface of the nucleosome and that selected amino acid residues are subject to a variety of enzyme-catalyzed, post-translational modifications. These include acetylation of lysines, phosphorylation of serines, and methylation of lysines and arginines ([6,7], see also chapters by Davie, and Ausio and Abbott, this volume). The locations of the histone N-terminal tails in the nucleosome and the residues that can be modified are shown in Fig. 1. 

OATP expression is controlled by similar nuclear factors to NTCP but, unlike NTCP, the activity is down-regulated by phosphorylation of serine... 

Phosphorylation of serine, threonine, and tyrosine side-chain OH groups of proteins by kinases and their dephosphorylation by protein phosphatases provides an important mechanism for biological regulation. Tyrosine phosphatases are not metalloenzymes but the serine/threonine phosphatases contain a bimetallic site. 

It has been shown that phosphorylation changes the local conformation of a protein and thereby affects the activity of the complete protein. 341 Phosphorylation of serine and threonine side chains often occurs (Scheme 2). Phosphoamino acids are readily characterized using 3H and 31P NMR experiments. The H and 31P NMR parameters are distinct for phosphorylated serine, threonine, and tyrosine and have also been used to identify both cis-and trans-O-phospho-4-hydroxy-L-proline. 35 Phosphorylation of Cys is rare, but it can be identified by NMR even in large proteins. 36 ... 

Phosphorylation of serine or threonine residues involves an ATP-dependent addition of a phosphate group to a primary (serine) or secondary (threonine) alcohol. Phos-phorylated proteins are often subject to rapid degradation. 

Kishimoto, A. Brown, M.S. Slaughter, C.A. Goldstein, J.L. Phosphorylation of serine 833 in cytoplasmic domain of low density lipoprotein receptor by a high molecular weight enzyme resembling casein kinase II. J. Biol. Chem., 262, 1344-1351 (1987)... 

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