4OUC

Structure of human haspin in complex with histone H3 substrate

Summary for 4OUC

• Entry DOI: 10.2210/pdb4ouc/pdb
• Descriptor: Serine/threonine-protein kinase haspin, Histone H3.2, SODIUM ION, ... (7 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, transferase, histone, kinase substrate complex, chromatin regulator
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q8TF76 Q71DI3
• Total number of polymer chains: 2
• Total formula weight: 43040.55

Authors

Chaikuad, A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2014-02-15, release date: 2014-04-16, Last modification date: 2023-09-20)

Primary citation

Maiolica, A.,de Medina-Redondo, M.,Schoof, E.M.,Chaikuad, A.,Villa, F.,Gatti, M.,Jeganathan, S.,Lou, H.J.,Novy, K.,Hauri, S.,Toprak, U.H.,Herzog, F.,Meraldi, P.,Penengo, L.,Turk, B.E.,Knapp, S.,Linding, R.,Aebersold, R.
Modulation of the chromatin phosphoproteome by the haspin protein kinase.
Mol Cell Proteomics, 13:1724-1740, 2014

PubMed 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.

PubMed: 24732914
DOI: 10.1074/mcp.M113.034819

Experimental method

X-RAY DIFFRACTION (1.9 Å)