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PDBsum entry 4gnf
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Transferase/nuclear protein
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PDB id
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4gnf
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References listed in PDB file
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Key reference
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Title
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The methyltransferase nsd3 has chromatin-Binding motifs, Phd5-C5hch, That are distinct from other nsd (nuclear receptor set domain) family members in their histone h3 recognition.
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Authors
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C.He,
F.Li,
J.Zhang,
J.Wu,
Y.Shi.
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Ref.
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J Biol Chem, 2013,
288,
4692-4703.
[DOI no: ]
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PubMed id
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Abstract
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The NSD (nuclear receptor SET domain-containing) family members, consisting of
NSD1, NSD2 (MMSET/WHSC1), and NSD3 (WHSC1L1), are SET domain-containing
methyltransferases and aberrant expression of each member has been implicated in
multiple diseases. They have specific mono- and dimethylase activities for
H3K36, whereas play nonredundant roles during development. Aside from the well
characterized catalytic SET domain, NSD proteins have multiple potential
chromatin-binding motifs that are clinically relevant, including the fifth plant
homeodomain (PHD5) and the adjacent Cys-His-rich domain (C5HCH) located at the C
terminus. Herein, we report the crystal structures of the PHD5-C5HCH module of
NSD3, in the free state and in complex with H3(1-7) (H3 residues 1-7), H3(1-15)
(H3 residues 1-15), and H3(1-15)K9me3 (H3 residues 1-15 with trimethylation on
K9) peptides. These structures reveal that the PHD5 and C5HCH domains fold into
a novel integrated PHD-PHD-like structural module with H3 peptide bound only on
the surface of PHD5 and provide the molecular basis for the recognition of
unmodified H3K4 and trimethylated H3K9 by NSD3 PHD5. Structural studies and
binding assays show that differences exist in histone binding specificity of the
PHD5 domain between three members of the NSD family. For NSD2, the PHD5-C5HCH:H3
N terminus interaction is largely conserved, although with a stronger preference
for unmethylated H3K9 (H3K9me0) than trimethylated H3K9 (H3K9me3), and NSD1
PHD5-C5HCH does not bind to H3 peptides. Our results shed light on how NSD
proteins that mediate H3K36 methylation are localized to specific genomic sites
and provide implications for the mechanism of functional diversity of NSD
proteins.
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