(Above) Overview of FOXC1 protein structure and functional protein domains identified by in vitro analyses. (Below) Amino acid sequence alignment of critical residues in the Forkhead domain of FOXC1 which are essential for the DNA-binding properties of FOX proteins. Residues highlighted in orange are indispensable for sequence-specific recognition of the FOX DNA motif, while those highlighted in blue promote non-specific engagement of nucleosomal DNA by FOXA proteins, consistent with pioneer activity [10,11]. AD, activating domain; DBD, Forkhead DNA-binding domain; ID, inhibitory domain; NLS, nuclear localization signal; hs, Homo sapiens.