FOXP3 recognizes microsatellites and bridges DNA through multimerization

Wenxiang Zhang, Fangwei Leng, Xi Wang, Ricardo N. Ramirez, Jinseok Park, Christophe Benoist and Sun Hur ()
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Wenxiang Zhang: Boston Children’s Hospital
Fangwei Leng: Boston Children’s Hospital
Xi Wang: Boston Children’s Hospital
Ricardo N. Ramirez: Harvard Medical School
Jinseok Park: Harvard Medical School
Christophe Benoist: Harvard Medical School
Sun Hur: Boston Children’s Hospital

Nature, 2023, vol. 624, issue 7991, 433-441

Abstract: Abstract FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity1–5. However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain—a DNA-binding domain that is commonly thought to function as a monomer or dimer—to form a higher-order multimer after binding to TnG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T3G repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two ‘side rails’ bridged by five pairs of FOXP3 molecules, with each pair forming a ‘rung’. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair TnG repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for TnG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TnG repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases.

Date: 2023
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DOI: 10.1038/s41586-023-06793-z

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