9vrq
Crystal structure of FOXC2/NFAT1 complex bound to ARRE2 DNA
Structural highlights
DiseaseFOXC2_HUMAN Defects in FOXC2 are the cause of lymphedema hereditary type 2 (LMPH2) [MIM:153200; also known as Meige lymphedema. Hereditary lymphedema is a chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections, and physical impairment.[1] Defects in FOXC2 are a cause of lymphedema-yellow nails (LYYN) [MIM:153300. LYYN is characterized by yellow, dystrophic, thick and slowly growing nails, associated with lymphedema and respiratory involvement. Lymphedema occurs more often in the lower limbs. It can appear at birth or later in life. Onset generally follows the onset of ungual abnormalities. Defects in FOXC2 are a cause of lymphedema-distichiasis (LYD) [MIM:153400. LYD is characterized by primary limb lymphedema usually starting at puberty (but in some cases later or at birth) and associated with distichiasis (double rows of eyelashes, with extra eyelashes growing from the Meibomian gland orifices).[2] FunctionFOXC2_HUMAN Transcriptional activator. Might be involved in the formation of special mesenchymal tissues.[3] Publication Abstract from PubMedTranscription factor nuclear factor of activated T cells (NFAT) plays a central role in immune gene regulation through cooperative interactions with diverse transcriptional partners. While FOXP family members have been identified as co-regulators of NFAT1, the involvement of other FOX family proteins has remained mechanistically obscure. Here, we solved three crystal structures of NFAT1-RHR/FOXC2-DBD/ARRE DNA ternary complexes and uncovered an unexpected mode of transcriptional repression mediated by FOXC2 through direct, DNA-facilitated binding to the V-shaped groove of NFAT1's Rel-homology region (RHR). Biochemical assays revealed that DNA enhanced FOXC2-NFAT1 interaction by more than five-fold, supporting a model in which DNA acts as a structural co-factor that promotes complex formation. Mutational disruption of the FOXC2-NFAT1 interface impaired complex assembly and abrogated transcriptional repression. Functional assays further confirmed that FOXC2 suppressed NFAT1-driven transcription of multiple cytokines and chemokines, including IL2, TNF, CXCL5, and CCL2. Notably, this repressive mechanism was found to extend to other FOX proteins (FOXI1, FOXO1, and FOXK1), suggesting a broader paradigm of FOX-NFAT1 interaction. Our study defined a previously unrecognized FOX-mediated transcriptional repression mechanism and provides a structural framework for NFAT inhibition by FOX proteins, offering novel insights into the transcriptional regulation of immune-related genes. FOXC2 represses NFAT1-dependent transcription through a DNA-facilitated protein-protein interaction.,Chen X, Wu S, Yue S, Zhang L, Liu X, Dai S, Li J, Zhang H, Wei H, Guo M, Qu L, Chen L, Deng Y, Chen Y Nucleic Acids Res. 2026 Apr 23;54(8):gkag367. doi: 10.1093/nar/gkag367. PMID:42023653[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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