Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner
Sung-Hak KimRavesanker EzhilarasanEmma PhillipsDaniel Gallego‐PerezAmanda SparksDavid TaylorKatherine J. LadnerTakuya FurutaHemragul SabitRishi Raj ChhipaJu Hwan ChoAhmed MohyeldinSamuel J. BeckKazuhiko KurozumiToshihiko KuroiwaRyoichi IwataAkio AsaiJonghwan KimErik P. SulmanShi‐Yuan ChengL. James LeeMitsutoshi NakadaDenis C. GuttridgeBiplab DasguptaViolaine GoidtsKrishna BhatIchiro Nakano
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OGlcNAcylation and phosphorylation are the major competing intracellular post-translational modifications of serine and threonine residues. The structural effects of both post-translational modifications on serine and threonine were examined within Baldwin model α-helical peptides (Ac-AKAAAAKAAAAKAAGY-NH2 or Ac-YGAKAAAAKAAAAKAA-NH2). At the N-terminus of an α-helix, both phosphorylation and OGlcNAcylation stabilized the α-helix relative to the free hydroxyls, with a larger induced structure for phosphorylation than for OGlcNAcylation, for the dianionic phosphate than for the monoanionic phosphate, and for modifications on threonine than for modifications on serine. Both phosphoserine and phosphothreonine resulted in peptides more α-helical than alanine at the N-terminus, with dianionic phosphothreonine the most α-helix-stabilizing residue here. In contrast, in the interior of the α-helix, both post-translational modifications were destabilizing with respect to the α-helix, with the greatest destabilization seen for threonine OGlcNAcylation at residue 5 and threonine phosphorylation at residue 10, with peptides containing either post-translational modification existing as random coils. At the C-terminus, both OGlcNAcylation and phosphorylation were destabilizing with respect to the α-helix, though the induced structural changes were less than in the interior of the α-helix. In general, the structural effects of modifications on threonine were greater than the effects on serine, because of both the lower α-helical propensity of Thr and the more defined induced structures upon modification of threonine than serine, suggesting threonine residues are particularly important loci for structural effects of post-translational modifications. The effects of serine and threonine post-translational modifications are analogous to the effects of proline on α-helices, with the effects of phosphothreonine being greater than those of proline throughout the α-helix. These results provide a basis for understanding the context-dependent structural effects of these competing protein post-translational modifications.
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Bovine submaxillary mucin (a glycoprotein) was hydrolyzed for varous times (1 to 300 hr) at 110° in 6 N HCl (0.3 mg protein per ml). The kinetics of destruction of serine were found to be first‐order and that of threonine to be zero‐order. The velocity constant for the destruction of serine was k – 4.3 X 10‐ 3 hr‐ 1 and of threonine was k – 5.6 X 10‐ 4 mole hr 1 . The amounts of serine and threonine destroyed after 22 hours hydrolysis were 10.0 % and 2.7 %, respectively. Since the losses were the same in the absence of carbohydrates and since several prior extensive investigations reported similar corrections for serine, these corrections may be applicable to most proteins and glycoproteins.
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Abstract L-serine, L-threonine and L-cysteine are useful optically active precursors for the asymmetric synthesis of a wide variety of molecules such as amino acids1-3 or other nitrogen-containing targets. Commercially available, they offer a great challenge to the synthetic chemist in terms of stereochemical control and efficiency. In particular, the preparation of various serine-, threonine- and cysteine-derived aldehydes for synthetic purposes requires four conditions: Carboxy group modifications are generally undertaken after suitable protection of the OH (or SH) and NH2 functionalities. The preparation of N protected a-amino aldehydes has received much attention in recent years.13 They are usually purified by vacuum distillation,
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Abstract Treatment of suitably protected serine and threonine derivatives with N,N‐diethylaminodibenzylphosphoramidite, followed by subsequent treatment with tert‐butyl hydroperoxide affords the phosphorylated amino acids in good yields. After deprotection and coupling with the hydroxybenzotriazole ester from Boc‐Ala the protected phosphopeptides are obtained in good yields.
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The synthesis of human growth hormone-releasing hormone (hGH-RH), by the chemoselective serine/threonine ligations (STLs) of three unprotected peptide fragments, is reported. To allow for the multiple-fragment ligation, we chose the Msz (p-(methylsulfinyl)benzyloxycarbonyl) group, which is compatible with the preparation of peptide salicylaldehyde esters via Fmoc-SPPS and readily removed by reductive acidolysis, to protect the serine and threonine residue at the N-terminus.
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Insulin promotes insulin receptor beta-subunit phosphorylation on tyrosine, serine, and threonine residues in a variety of cells, including simian COS cells which transiently express human insulin receptors following transfection with a cDNA encoding the wild-type receptor protein. To examine the potential roles of serines 1305 and 1306 and threonine 1348 as sites of insulin-stimulated phosphorylation in these cells, these residues (i.e. either serines 1305 and 1306, or threonine 1348) were replaced with neutral (alanine) or negatively charged (aspartate) amino acids. Following transient expression of each of these mutant receptors in COS cells, two-dimensional phosphopeptide mapping reveals that threonine 1348 is the major, if not the only, insulin-stimulated threonine phosphorylation site. In contrast, while serines 1305 and/or 1306 are phosphorylated in an insulin-dependent manner, these sites comprise only a minor proportion of insulin receptor serine phosphorylation in these cells. Substitution of either serines 1305 and 1306 or threonine 1348 with neutral or negatively charged amino acids has no effect on insulin-stimulated tyrosine autophosphorylation of these mutant receptors in intact cells. Furthermore, insulin-stimulated exogenous protein-tyrosine kinase activity of the mutant receptors is unaffected, as assessed following either phosphorylation of receptors in intact cells or following immunopurification of receptors and their autophosphorylation in vitro.
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Abstract The molecular weights of four linear synthetic peptides, fragments of a snake α‐neurotoxin, were measured by 252 Cf‐plasma desorption mass spectrometry. The fragmentation phenomenon observed at the level of serine and/or threonine residue with a concomitant ion/fragment association is reported for a group of two peptides (B and D) in contrast with the group (A and C) in spite of the high ratio of serine and threonine, namely peptide A. The propensity for specific fragmentation of peptide D seems to be correlated to the repetitive sequence, (Gly‐Ser) 2 . Finally, based on the m/z of the daughter‐ions measured, we propose an overall mechanism as an N→O acyl shift analogous to that observed for serine‐ and threonine‐ containing peptides in solution chemistry.
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F. Bergel and R. Wade, J. Chem. Soc., 1959, 941 DOI: 10.1039/JR9590000941
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To study the sequence requirements for addition of O-linked N-acetylgalactosamine to proteins, amino acid distributions around 174 O-glycosylation sites were compared with distributions around non-glycosylated sites. In comparison with non-glycosylated serine and threonine residues, the most prominent feature in the vicinity of O-glycosylated sites is a significantly increased frequency of proline residues, especially at positions -1 and +3 relative to the glycosylated residues. Alanine, serine and threonine are also significantly increased. The high serine and threonine content of O-glycosylated regions is due to the presence of clusters of several closely spaced glycosylated hydroxy amino acids in many O-glycosylated proteins. Such clusters can be predicted from the primary sequence in some cases, but there is no apparent possibility of predicting isolated O-glycosylation sites from primary sequence data.
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