The FOXP2 forkhead domain binds to a variety of DNA sequences with different rates and affinities

• Published in: Journal of biochemistry (Tokyo) 2017-07, Vol.162 (1), p.45-54
• Main Authors: Webb, Helen, Steeb, Olga, Blane, Ashleigh, Rotherham, Lia, Aron, Shaun, Machanick, Philip, Dirr, Heini, Fanucchi, Sylvia
• Format: Article
• Language: English
• Subjects: Base Sequence; Binding Sites; DNA - genetics; DNA - metabolism; Forkhead Transcription Factors - chemistry; Forkhead Transcription Factors - metabolism; Humans; Models, Molecular; Protein Domains; Surface Plasmon Resonance
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvx003

FOXP2 is a member of the P subfamily of FOX transcription factors, the DNA-binding domain of which is the winged helix forkhead domain (FHD). In this work we show that the FOXP2 FHD is able to bind to various DNA sequences, including a novel sequence identified in this work, with different affinities and rates as detected using surface plasmon resonance. Combining the experimental work with molecular docking, we show that high-affinity sequences remain bound to the protein for longer, form a greater number of interactions with the protein and induce a greater structural change in the protein than low-affinity sequences. We propose a binding model for the FOXP2 FHD that involves three types of binding sequence: low affinity sites which allow for rapid scanning of the genome by the protein in a partially unstructured state; moderate affinity sites which serve to locate the protein near target sites and high-affinity sites which secure the protein to the DNA and induce a conformational change necessary for functional binding and the possible initiation of downstream transcriptional events.