Structural and Biological Features of FOXP3 Dimerization Relevant to Regulatory T Cell Function
Xiaomin Song,
Bin Li,
Yan Xiao,
Chunxia Chen,
Qiang Wang,
Yujie Liu,
Alan Berezov,
Chen Xu,
Yayi Gao,
Zhiyuan Li,
Shiaw-Lin Wu,
Zheng Cai,
Hongtao Zhang,
Barry L. Karger,
Wayne W. Hancock,
Andrew D. Wells,
Zhaocai Zhou,
Mark I. Greene
Affiliations
Xiaomin Song
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China 200031
Bin Li
Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 200031
Yan Xiao
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Chunxia Chen
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Qiang Wang
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Yujie Liu
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Alan Berezov
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Chen Xu
Rosentiel Basic Medical Research Center, Brandeis University, Waltham, MA 02453, USA
Yayi Gao
Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 200031
Zhiyuan Li
Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 200031
Shiaw-Lin Wu
Barnett Institute, Northeastern University, Boston, MA 02115, USA
Zheng Cai
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hongtao Zhang
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Barry L. Karger
Barnett Institute, Northeastern University, Boston, MA 02115, USA
Wayne W. Hancock
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Andrew D. Wells
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Zhaocai Zhou
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China 200031
Mark I. Greene
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
FOXP3 is a key transcription factor for regulatory T cell function. We report the crystal structure of the FOXP3 coiled-coil domain, through which a loose or transient dimeric association is formed and modulated, accounting for the activity variations introduced by disease-causing mutations or posttranslational modifications. Structure-guided mutagenesis revealed that FOXP3 coiled-coil-mediated homodimerization is essential for Treg function in vitro and in vivo. In particular, we identified human FOXP3 K250 and K252 as key residues for the conformational change and stability of the FOXP3 dimer, which can be regulated by protein posttranslational modifications such as reversible lysine acetylation. These studies provide structural and mechanistic explanations for certain disease-causing mutations in the coiled-coil domain of FOXP3 that are commonly found in IPEX syndrome. Overall, the regulatory machinery involving homooligomerization, acetylation, and heteroassociation has been dissected, defining atomic insights into the biological and pathological characteristics of the FOXP3 complex.
