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Crystal Structure of STAT3 N-terminal domain
Structural highlights
FunctionSTAT3_MOUSE Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF and other growth factors. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. Binds to the interleukin-6 (IL-6)-responsive elements identified in the promoters of various acute-phase protein genes. Activated by IL31 through IL31RA. STAT3B interacts with the N-terminal part of JUN to activate such promoters in a cooperative way.[1] Publication Abstract from PubMedThe 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 or NTD-deleted STAT3. NTD deletion reduced cytokine-induced expression of specific STAT3 target genes by decreasing STAT3 binding to their regulatory regions. To better understand 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 a Ni2+-mediated oligomer with as yet unknown biological function. Mutations on both dimer and Ni2+-mediated interfaces affected cytokine induction of STAT3 target genes. These studies shed light on the role of the NTD in the transcriptional regulation by STAT3 and provide a structural template to design STAT3 NTD inhibitors with potential therapeutic value. Impact of the N-terminal domain of STAT3 in STAT3-dependent transcriptional activity.,Hu T, Yeh JE, Pinello L, Jacob J, Chakravarthy S, Yuan GC, Chopra R, Frank DA Mol Cell Biol. 2015 Jul 13. pii: MCB.00060-15. PMID:26169829[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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