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PDBsum entry 4ouc
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References listed in PDB file
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Key reference
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Title
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Modulation of the chromatin phosphoproteome by the haspin protein kinase.
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Authors
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A.Maiolica,
M.De medina-Redondo,
E.M.Schoof,
A.Chaikuad,
F.Villa,
M.Gatti,
S.Jeganathan,
H.J.Lou,
K.Novy,
S.Hauri,
U.H.Toprak,
F.Herzog,
P.Meraldi,
L.Penengo,
B.E.Turk,
S.Knapp,
R.Linding,
R.Aebersold.
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Ref.
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Mol Cell Proteomics, 2014,
13,
1724-1740.
[DOI no: ]
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PubMed id
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Abstract
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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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