Structural basis for DNA recognition by STAT6

doi:10.1073/pnas.1611228113

	Structural basis for DNA recognition by STAT6
	Li, Jing 1,2; Rodriguez, Jose Pindado 3; Niu, Fengfeng 1; Pu, Mengchen 1; Wang, Jinan 4; Hung, Li-Wei 5; Shao, Qiang 4; Zhu, Yanping 1; Ding, Wei 1; Liu, Yanqing 1; Da, Yurong 6; Yao, Zhi 6; Yang, Jie 6; Zhao, Yongfang 1; Wei, Gong-Hong 7,8; Cheng, Genhong 3; Liu, Zhi-Jie1,6,9,10 ; Ouyang, Songying 1,3
	2016-11-15
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN	0027-8424
卷号	113 期号:46 页码:13015-13020
发表状态	已发表
DOI	10.1073/pnas.1611228113
摘要	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(CF)) 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 STAT6CF 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.
关键词	STAT6 N4 site DNA recognition JAK-STAT pathway antiviral innate immunity crystal structure
收录类别	SCI
语种	英语
资助项目	Youth Innovation Promotion Association Chinese Academy of Sciences[2013065]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000388970100052
出版者	NATL ACAD SCIENCES
WOS关键词	TRANSCRIPTIONAL ACTIVITY ; UNPHOSPHORYLATED STAT1 ; CRYSTAL-STRUCTURE ; SH2 DOMAIN ; BINDING ; DIMER ; REVEALS ; COMPLEX ; PROTEIN ; SITES
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1059
专题	iHuman研究所_PI研究组_刘志杰组 iHuman研究所
通讯作者	Ouyang, Songying
作者单位	1.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Key Lab Receptor Res, Shanghai 201203, Peoples R China 5.Los Alamos Natl Lab, Phys Div, Los Alamos, NM 87545 USA 6.Tianjin Med Univ, Dept Immunol, Tianjin 300070, Peoples R China 7.Univ Oulu, Bioctr Oulu, SF-90220 Oulu, Finland 8.Univ Oulu, Fac Biochem & Mol Med, SF-90220 Oulu, Finland 9.Shanghai Tech Univ, iHuman Inst, Shanghai 201210, Peoples R China 10.Kunming Med Univ, Inst Mol & Clin Med, Kunming 650500, Peoples R China
推荐引用方式 GB/T 7714	Li, Jing,Rodriguez, Jose Pindado,Niu, Fengfeng,et al. Structural basis for DNA recognition by STAT6[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2016,113(46):13015-13020.
APA	Li, Jing.,Rodriguez, Jose Pindado.,Niu, Fengfeng.,Pu, Mengchen.,Wang, Jinan.,...&Ouyang, Songying.(2016).Structural basis for DNA recognition by STAT6.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,113(46),13015-13020.
MLA	Li, Jing,et al."Structural basis for DNA recognition by STAT6".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113.46(2016):13015-13020.