FoxP1 is a multidomain transcription factor implicated in development, immunity, and cancer, widely proposed to function as a dimer. However, the molecular mechanisms governing its assembly and nuclear organization in living cells remain unclear. Here, we combine biochemical assays and live-cell fluorescence lifetime imaging to resolve FoxP1 homotypic interactions. We show that FoxP1 forms heterogeneous complexes whose stability is governed by antagonistic coupling between its leucine-zipper (ZIP) and Forkhead (FKH) domains. The FoxP1 ZIP domain promotes dimerization while suppressing FKH-mediated interactions, revealing a competing interdomain mechanism that tunes complex formation. Pathogenic and deletion variants disrupt this intricate balance, altering interaction stability and promoting the formation of dense nuclear condensates upon loss of DNA binding. Together, our results demonstrate that FoxP1 assembly is encoded by its multidomain architecture. Our findings show how competing interaction domains regulate transcription factor complex formation, nuclear organization, and DNA binding, with implications for disease-associated dysregulation.
Lazaro-Alfaro, A. F., Aviles, J., Peulen, T.-O., Medina, E. A., Heinze, K., Sanabria, H., Hemmen, K.
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