title: Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells.
abstract: The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoimmunity observed in IPEX patients.
authors: Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.
authors: Hozefa S
authors: HS
authors: Bandukwala
authors: Yongqing
authors: Y
authors: Wu
authors: Markus
authors: M
authors: Feuerer
authors: Yongheng
authors: Y
authors: Chen
authors: Bianca
authors: B
authors: Barboza
authors: Srimoyee
authors: S
authors: Ghosh
authors: James C
authors: JC
authors: Stroud
authors: Christophe
authors: C
authors: Benoist
authors: Diane
authors: D
authors: Mathis
authors: Anjana
authors: A
authors: Rao
authors: Lin
authors: L
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051858:Forkhead Transcription Factors / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000276:immunology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry* / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050778:NFATC Transcription Factors