Modulation of the chromatin phosphoproteome by the Haspin protein kinase
Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr(3) of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date,...
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| Vydáno v: | Molecular & cellular proteomics Ročník 13; číslo 7; s. 1724 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.07.2014
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| ISSN: | 1535-9484, 1535-9484 |
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| Abstract | Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr(3) of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date, histone H3 is the only confirmed Haspin substrate. We used a combination of biochemical, pharmacological, and mass spectrometric approaches to study the consequences of Haspin inhibition in mitotic cells. We quantified 3964 phosphorylation sites on chromatin-associated proteins and identified a Haspin protein-protein interaction network. We determined the Haspin consensus motif and the co-crystal structure of the kinase with the histone H3 tail. The structure revealed a unique bent substrate binding mode positioning the histone H3 residues Arg(2) and Lys(4) adjacent to the Haspin phosphorylated threonine into acidic binding pockets. This unique conformation of the kinase-substrate complex explains the reported modulation of Haspin activity by methylation of Lys(4) of the histone H3. In addition, the identification of the structural basis of substrate recognition and the amino acid sequence preferences of Haspin aided the identification of novel candidate Haspin substrates. In particular, we validated the phosphorylation of Ser(137) of the histone variant macroH2A as a target of Haspin kinase activity. MacroH2A Ser(137) resides in a basic stretch of about 40 amino acids that is required to stabilize extranucleosomal DNA, suggesting that phosphorylation of Ser(137) might regulate the interactions of macroH2A and DNA. Overall, our data suggest that Haspin activity affects the phosphorylation state of proteins involved in gene expression regulation and splicing. |
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| AbstractList | Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr(3) of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date, histone H3 is the only confirmed Haspin substrate. We used a combination of biochemical, pharmacological, and mass spectrometric approaches to study the consequences of Haspin inhibition in mitotic cells. We quantified 3964 phosphorylation sites on chromatin-associated proteins and identified a Haspin protein-protein interaction network. We determined the Haspin consensus motif and the co-crystal structure of the kinase with the histone H3 tail. The structure revealed a unique bent substrate binding mode positioning the histone H3 residues Arg(2) and Lys(4) adjacent to the Haspin phosphorylated threonine into acidic binding pockets. This unique conformation of the kinase-substrate complex explains the reported modulation of Haspin activity by methylation of Lys(4) of the histone H3. In addition, the identification of the structural basis of substrate recognition and the amino acid sequence preferences of Haspin aided the identification of novel candidate Haspin substrates. In particular, we validated the phosphorylation of Ser(137) of the histone variant macroH2A as a target of Haspin kinase activity. MacroH2A Ser(137) resides in a basic stretch of about 40 amino acids that is required to stabilize extranucleosomal DNA, suggesting that phosphorylation of Ser(137) might regulate the interactions of macroH2A and DNA. Overall, our data suggest that Haspin activity affects the phosphorylation state of proteins involved in gene expression regulation and splicing. Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr(3) of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date, histone H3 is the only confirmed Haspin substrate. We used a combination of biochemical, pharmacological, and mass spectrometric approaches to study the consequences of Haspin inhibition in mitotic cells. We quantified 3964 phosphorylation sites on chromatin-associated proteins and identified a Haspin protein-protein interaction network. We determined the Haspin consensus motif and the co-crystal structure of the kinase with the histone H3 tail. The structure revealed a unique bent substrate binding mode positioning the histone H3 residues Arg(2) and Lys(4) adjacent to the Haspin phosphorylated threonine into acidic binding pockets. This unique conformation of the kinase-substrate complex explains the reported modulation of Haspin activity by methylation of Lys(4) of the histone H3. In addition, the identification of the structural basis of substrate recognition and the amino acid sequence preferences of Haspin aided the identification of novel candidate Haspin substrates. In particular, we validated the phosphorylation of Ser(137) of the histone variant macroH2A as a target of Haspin kinase activity. MacroH2A Ser(137) resides in a basic stretch of about 40 amino acids that is required to stabilize extranucleosomal DNA, suggesting that phosphorylation of Ser(137) might regulate the interactions of macroH2A and DNA. Overall, our data suggest that Haspin activity affects the phosphorylation state of proteins involved in gene expression regulation and splicing.Recent discoveries have highlighted the importance of Haspin kinase activity for the correct positioning of the kinase Aurora B at the centromere. Haspin phosphorylates Thr(3) of the histone H3 (H3), which provides a signal for Aurora B to localize to the centromere of mitotic chromosomes. To date, histone H3 is the only confirmed Haspin substrate. We used a combination of biochemical, pharmacological, and mass spectrometric approaches to study the consequences of Haspin inhibition in mitotic cells. We quantified 3964 phosphorylation sites on chromatin-associated proteins and identified a Haspin protein-protein interaction network. We determined the Haspin consensus motif and the co-crystal structure of the kinase with the histone H3 tail. The structure revealed a unique bent substrate binding mode positioning the histone H3 residues Arg(2) and Lys(4) adjacent to the Haspin phosphorylated threonine into acidic binding pockets. This unique conformation of the kinase-substrate complex explains the reported modulation of Haspin activity by methylation of Lys(4) of the histone H3. In addition, the identification of the structural basis of substrate recognition and the amino acid sequence preferences of Haspin aided the identification of novel candidate Haspin substrates. In particular, we validated the phosphorylation of Ser(137) of the histone variant macroH2A as a target of Haspin kinase activity. MacroH2A Ser(137) resides in a basic stretch of about 40 amino acids that is required to stabilize extranucleosomal DNA, suggesting that phosphorylation of Ser(137) might regulate the interactions of macroH2A and DNA. Overall, our data suggest that Haspin activity affects the phosphorylation state of proteins involved in gene expression regulation and splicing. |
| Author | Knapp, Stefan de Medina-Redondo, Maria Turk, Benjamin E Toprak, Umut H Schoof, Erwin M Aebersold, Ruedi Maiolica, Alessio Gatti, Marco Novy, Karel Jeganathan, Siva Penengo, Lorenza Linding, Rune Chaikuad, Apirat Villa, Fabrizio Lou, Hua Jane Herzog, Franz Hauri, Simon Meraldi, Patrick |
| Author_xml | – sequence: 1 givenname: Alessio surname: Maiolica fullname: Maiolica, Alessio organization: From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland – sequence: 2 givenname: Maria surname: de Medina-Redondo fullname: de Medina-Redondo, Maria organization: §Department of Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland – sequence: 3 givenname: Erwin M surname: Schoof fullname: Schoof, Erwin M organization: ¶Cellular Signal Integration Group (C-SIG), Center for Biological Sequence Analysis (CBS), Department of Systems Biology, Technical University of Denmark (DTU), Lyngby, Denmark – sequence: 4 givenname: Apirat surname: Chaikuad fullname: Chaikuad, Apirat organization: ‖Oxford University, Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI) and Structural Genomics Consortium (SGC), Oxford OX3 7FZ, United Kingdom – sequence: 5 givenname: Fabrizio surname: Villa fullname: Villa, Fabrizio organization: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy – sequence: 6 givenname: Marco surname: Gatti fullname: Gatti, Marco organization: ‡‡Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro" Novara, Italy – sequence: 7 givenname: Siva surname: Jeganathan fullname: Jeganathan, Siva organization: §§Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany – sequence: 8 givenname: Hua Jane surname: Lou fullname: Lou, Hua Jane organization: ¶¶Yale University School of Medicine, Department of Pharmacology, New Haven, Connecticut 06520, USA – sequence: 9 givenname: Karel surname: Novy fullname: Novy, Karel organization: From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland – sequence: 10 givenname: Simon surname: Hauri fullname: Hauri, Simon organization: From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland – sequence: 11 givenname: Umut H surname: Toprak fullname: Toprak, Umut H organization: §Department of Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland – sequence: 12 givenname: Franz surname: Herzog fullname: Herzog, Franz organization: ‖‖Gene Center Munich Ludwig-Maximilians-Universität München, Munich, Germany – sequence: 13 givenname: Patrick surname: Meraldi fullname: Meraldi, Patrick organization: §Department of Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland – sequence: 14 givenname: Lorenza surname: Penengo fullname: Penengo, Lorenza organization: ‡‡Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro" Novara, Italy – sequence: 15 givenname: Benjamin E surname: Turk fullname: Turk, Benjamin E organization: ¶¶Yale University School of Medicine, Department of Pharmacology, New Haven, Connecticut 06520, USA – sequence: 16 givenname: Stefan surname: Knapp fullname: Knapp, Stefan organization: ‖Oxford University, Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI) and Structural Genomics Consortium (SGC), Oxford OX3 7FZ, United Kingdom – sequence: 17 givenname: Rune surname: Linding fullname: Linding, Rune organization: ¶Cellular Signal Integration Group (C-SIG), Center for Biological Sequence Analysis (CBS), Department of Systems Biology, Technical University of Denmark (DTU), Lyngby, Denmark – sequence: 18 givenname: Ruedi surname: Aebersold fullname: Aebersold, Ruedi email: aebersold@imsb.biol.ethz.ch organization: From the ‡Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland; Faculty of Science, University of Zurich, Zurich, Switzerland aebersold@imsb.biol.ethz.ch |
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| SubjectTerms | Amino Acid Sequence Aurora Kinase B - metabolism Cell Line, Tumor Chromatin - genetics Chromatin - metabolism Gene Expression Regulation - genetics HEK293 Cells HeLa Cells Histones - genetics Histones - metabolism Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Methylation Mitosis - genetics Nuclear Proteins - metabolism Phosphoproteins - metabolism Phosphorylation Protein Interaction Maps - genetics Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism RNA-Binding Proteins - metabolism Serine-Arginine Splicing Factors Transcription, Genetic - genetics |
| Title | Modulation of the chromatin phosphoproteome by the Haspin protein kinase |
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