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FOXP3 recognizes microsatellites and bridges DNA through multimerization.
- Source :
-
Nature [Nature] 2023 Dec; Vol. 624 (7991), pp. 433-441. Date of Electronic Publication: 2023 Nov 29. - Publication Year :
- 2023
-
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 <superscript>1-5</superscript> . 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 T <subscript>n</subscript> G repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T <subscript>3</subscript> G 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 T <subscript>n</subscript> G 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 T <subscript>n</subscript> G-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar T <subscript>n</subscript> G 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.<br /> (© 2023. The Author(s).)
- Subjects :
- Base Sequence
Consensus Sequence
Cryoelectron Microscopy
Mutation
Nucleotide Motifs
Protein Domains
Protein Multimerization
T-Lymphocytes, Regulatory metabolism
DNA chemistry
DNA genetics
DNA metabolism
DNA ultrastructure
Forkhead Transcription Factors chemistry
Forkhead Transcription Factors metabolism
Forkhead Transcription Factors ultrastructure
Microsatellite Repeats genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 624
- Issue :
- 7991
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38030726
- Full Text :
- https://doi.org/10.1038/s41586-023-06793-z