7TDX

Structure of FOXP3-DNA complex

Summary for 7TDX

• Entry DOI: 10.2210/pdb7tdx/pdb
• Descriptor: DNA (5'-D(*AP*AP*AP*TP*TP*TP*GP*TP*TP*TP*AP*CP*TP*C)-3'), DNA (5'-D(P*GP*AP*GP*TP*AP*AP*AP*CP*AP*AP*AP*TP*TP*T)-3'), Forkhead box P3 (3 entities in total)
• Functional Keywords: foxp3, dimer, forkhead, dna, treg, transcription-dna complex, transcription/dna
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 3
• Total formula weight: 29475.51

Authors

Leng, F.,Hur, S. (deposition date: 2022-01-03, release date: 2022-08-10, Last modification date: 2023-10-18)

Primary citation

Leng, F.,Zhang, W.,Ramirez, R.N.,Leon, J.,Zhong, Y.,Hou, L.,Yuki, K.,van der Veeken, J.,Rudensky, A.Y.,Benoist, C.,Hur, S.
The transcription factor FoxP3 can fold into two dimerization states with divergent implications for regulatory T cell function and immune homeostasis.
Immunity, 55:1354-, 2022

PubMed Abstract: FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions.

PubMed: 35926508
DOI: 10.1016/j.immuni.2022.07.002

Experimental method

X-RAY DIFFRACTION (3.1 Å)