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PDBsum entry 4zia
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Transcription
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PDB id
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4zia
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References listed in PDB file
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Key reference
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Title
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Impact of the n-Terminal domain of stat3 in stat3-Dependent transcriptional activity.
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Authors
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T.Hu,
J.E.Yeh,
L.Pinello,
J.Jacob,
S.Chakravarthy,
G.C.Yuan,
R.Chopra,
D.A.Frank.
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Ref.
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Mol Cell Biol, 2015,
35,
3284-3300.
[DOI no: ]
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PubMed id
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Abstract
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The transcription factor STAT3 is constitutively active in many cancers, where
it mediates important biological effects, including cell proliferation,
differentiation, survival, and angiogenesis. The N-terminal domain (NTD) of
STAT3 performs multiple functions, such as cooperative DNA binding, nuclear
translocation, and protein-protein interactions. However, it is unclear which
subsets of STAT3 target genes depend on the NTD for transcriptional regulation.
To identify such genes, we compared gene expression in STAT3-null mouse
embryonic fibroblasts (MEFs) stably expressing wild-type STAT3 or STAT3 from
which NTD was deleted. NTD deletion reduced the cytokine-induced expression of
specific STAT3 target genes by decreasing STAT3 binding to their regulatory
regions. To better understand the potential mechanisms of this effect, we
determined the crystal structure of the STAT3 NTD and identified a dimer
interface responsible for cooperative DNA binding in vitro. We also observed an
Ni(2+)-mediated oligomer with an as yet unknown biological function. Mutations
on both dimer and Ni(2+)-mediated interfaces affected the cytokine induction of
STAT3 target genes. These studies shed light on the role of the NTD in
transcriptional regulation by STAT3 and provide a structural template with which
to design STAT3 NTD inhibitors with potential therapeutic value.
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