Forkhead Domain Transcription Factors

Forkhead transcription factors are a subfamily of the winged helix-turn-helix DNA-binding domain superfamily. These transcription factors are named after the fork head mutant of D. melanogaster. All members of this subfamily contain a Forkhead domain (FHD) consisting of three amino-terminal alpha-helices, three beta strands, and two loops. The peculiar folding of the loops around the helices resembles butterfly wings and accounts for the 'winged helix' nickname. The Forkhead transcription factors have an in vitro consensus DNA-binding sequence, which is [5'-(G/A)(T/C)(A/C)AA(C/T)A-3']. The third alpha helix of the FHD is responsible for specific DNA-binding, which occurs in the DNA major groove. DNA-binding specificity also depends on the variable region at the helix 2,3 junction and the two loops that interact with bases in the DNA minor groove. Forkhead transcription factors are effectors of many signaling pathways including TGF-beta, MAPK, Shh, Wnt/beta-Catenin, and insulin/IGF. Importantly, mutations in different family members can cause ocular development abnormalities, severe immune defects, premature ovarian failure, mental retardation, autism, and speech disorders.