Structural insights into FOXP2 multimerization and interactions from AlphaFold3 modeling

FOXP2 is a transcription factor critical for speech and language, yet its full-length structure remains unresolved experimentally. We used AlphaFold3 to model full-length human FOXP2 and its complexes. AlphaFold3 predicts that FOXP2 forms a symmetric homo-hexamer, in which oligomerization orders regions that are disordered in the monomer. This assembly may facilitate cooperative DNA binding via the forkhead DNA-binding domains (FHDs). The FHD shows variable sequence affinities; high-affinity sites yield broader interfaces and greater stabilization, consistent with SPR data. Mapping of disease variants and human-specific substitutions revealed clustering in regions predicted to be stabilized by hexamer assembly. Modeling the R553H mutation showed loss of DNA contact at a critical recognition helix, which may explain its impact on transcription. We modeled FOXP2 interactions with 12 partners using AlphaFold3-multimer, evaluating interface consistency across replicates. DNA-dependent interactions were predicted with FOXP1, FOXP4, Pin1, and CDK3, involving the LZ and zinc finger domains. Other predicted interactions were low-confidence and sensitive to FOXP2’s dynamic behavior. This work generates a testable, in silico structure-function map of FOXP2 that provides a framework for future experimental validation.