Modulation of the chromatin phosphoproteome by the haspin protein kinase

Alessio Maiolica, Maria De Medina-Redondo, Erwin M. Schoof, Apirat Chaikuad, Fabrizio Villa, Marco Gatti, Siva Jeganathan, Hua Jane Lou, Karel Novy, Simon Hauri, Umut H. Toprak, Franz Herzog, Patrick Meraldi, Lorenza Penengo, Benjamin E. Turk, Stefan Knapp, Rune Linding, Ruedi Aebersoldab

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 Thr3 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 Arg2 and Lys4 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 Lys4 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 Ser137 resides in a basic stretch of about 40 amino acids that is required to stabilize extranucleosomal DNA, suggesting that phosphorylation of Ser137 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.

Original languageEnglish
Pages (from-to)1724-1740
Number of pages17
JournalMolecular and Cellular Proteomics
Volume13
Issue number7
DOIs
Publication statusPublished - 2014

Fingerprint

Histones
Protein Kinases
Chromatin
Phosphorylation
Modulation
Phosphotransferases
Centromere
Substrates
Aurora Kinase B
Gene expression regulation
Proteins
Protein Interaction Maps
DNA
Gene Expression Regulation
Amino Acids
Threonine
Methylation
Chromosomes
Amino Acid Sequence
Conformations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Analytical Chemistry

Cite this

Maiolica, A., De Medina-Redondo, M., Schoof, E. M., Chaikuad, A., Villa, F., Gatti, M., ... Aebersoldab, R. (2014). Modulation of the chromatin phosphoproteome by the haspin protein kinase. Molecular and Cellular Proteomics, 13(7), 1724-1740. https://doi.org/10.1074/mcp.M113.034819

Modulation of the chromatin phosphoproteome by the haspin protein kinase. / Maiolica, Alessio; De Medina-Redondo, Maria; Schoof, Erwin M.; Chaikuad, Apirat; Villa, Fabrizio; Gatti, Marco; Jeganathan, Siva; Lou, Hua Jane; Novy, Karel; Hauri, Simon; Toprak, Umut H.; Herzog, Franz; Meraldi, Patrick; Penengo, Lorenza; Turk, Benjamin E.; Knapp, Stefan; Linding, Rune; Aebersoldab, Ruedi.

In: Molecular and Cellular Proteomics, Vol. 13, No. 7, 2014, p. 1724-1740.

Research output: Contribution to journalArticle

Maiolica, A, De Medina-Redondo, M, Schoof, EM, Chaikuad, A, Villa, F, Gatti, M, Jeganathan, S, Lou, HJ, Novy, K, Hauri, S, Toprak, UH, Herzog, F, Meraldi, P, Penengo, L, Turk, BE, Knapp, S, Linding, R & Aebersoldab, R 2014, 'Modulation of the chromatin phosphoproteome by the haspin protein kinase', Molecular and Cellular Proteomics, vol. 13, no. 7, pp. 1724-1740. https://doi.org/10.1074/mcp.M113.034819
Maiolica A, De Medina-Redondo M, Schoof EM, Chaikuad A, Villa F, Gatti M et al. Modulation of the chromatin phosphoproteome by the haspin protein kinase. Molecular and Cellular Proteomics. 2014;13(7):1724-1740. https://doi.org/10.1074/mcp.M113.034819
Maiolica, Alessio ; De Medina-Redondo, Maria ; Schoof, Erwin M. ; Chaikuad, Apirat ; Villa, Fabrizio ; Gatti, Marco ; Jeganathan, Siva ; Lou, Hua Jane ; Novy, Karel ; Hauri, Simon ; Toprak, Umut H. ; Herzog, Franz ; Meraldi, Patrick ; Penengo, Lorenza ; Turk, Benjamin E. ; Knapp, Stefan ; Linding, Rune ; Aebersoldab, Ruedi. / Modulation of the chromatin phosphoproteome by the haspin protein kinase. In: Molecular and Cellular Proteomics. 2014 ; Vol. 13, No. 7. pp. 1724-1740.
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AU - Jeganathan, Siva

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AU - Herzog, Franz

AU - Meraldi, Patrick

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