8SRO

FoxP3 tetramer on TTTG repeats

Summary for 8SRO

• Entry DOI: 10.2210/pdb8sro/pdb
• EMDB information: 40736
• Descriptor: Forkhead box protein P3, DNA 72-mer (3 entities in total)
• Functional Keywords: foxp3, strs, transcriptional factor, fkh, transcription, transcription-dna complex, transcription/dna
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 8
• Total formula weight: 197890.24

Authors

Leng, F.,Hur, S. (deposition date: 2023-05-05, release date: 2023-10-18, Last modification date: 2023-12-27)

Primary citation

Zhang, W.,Leng, F.,Wang, X.,Ramirez, R.N.,Park, J.,Benoist, C.,Hur, S.
FOXP3 recognizes microsatellites and bridges DNA through multimerization.
Nature, 624:433-441, 2023

PubMed 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 autoimmunity. 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 TG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with TG 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 TG 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 TG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TG 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.

PubMed: 38030726
DOI: 10.1038/s41586-023-06793-z

Experimental method

ELECTRON MICROSCOPY (3.3 Å)