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Structural basis for DNA recognition by STAT6.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Nov 15; Vol. 113 (46), pp. 13015-13020. Date of Electronic Publication: 2016 Nov 01. - Publication Year :
- 2016
-
Abstract
- STAT6 participates in classical IL-4/IL-13 signaling and stimulator of interferon genes-mediated antiviral innate immune responses. Aberrations in STAT6-mediated signaling are linked to development of asthma and diseases of the immune system. In addition, STAT6 remains constitutively active in multiple types of cancer. Therefore, targeting STAT6 is an attractive proposition for treating related diseases. Although a lot is known about the role of STAT6 in transcriptional regulation, molecular details on how STAT6 recognizes and binds specific segments of DNA to exert its function are not clearly understood. Here, we report the crystal structures of a homodimer of phosphorylated STAT6 core fragment (STAT6 <superscript>CF</superscript> ) alone and bound with the N3 and N4 DNA binding site. Analysis of the structures reveals that STAT6 undergoes a dramatic conformational change on DNA binding, which was further validated by performing molecular dynamics simulation studies and small angle X-ray scattering analysis. Our data show that a larger angle at the intersection where the two protomers of STAT meet and the presence of a unique residue, H415, in the DNA-binding domain play important roles in discrimination of the N4 site DNA from the N3 site by STAT6. H415N mutation of STAT6 <superscript>CF</superscript> decreased affinity of the protein for the N4 site DNA, but increased its affinity for N3 site DNA, both in vitro and in vivo. Results of our structure-function studies on STAT6 shed light on mechanism of DNA recognition by STATs in general and explain the reasons underlying STAT6's preference for N4 site DNA over N3.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Binding Sites
Crystallization
DNA chemistry
Escherichia coli genetics
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Mutation
Protein Binding
Protein Conformation
Protein Multimerization
STAT6 Transcription Factor genetics
DNA metabolism
STAT6 Transcription Factor chemistry
STAT6 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27803324
- Full Text :
- https://doi.org/10.1073/pnas.1611228113