title: The FOXP2 forkhead domain binds to a variety of DNA sequences with different rates and affinities.
abstract: 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.
authors.affiliation: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: Webb
authors.affiliation: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
authors.forename: Olga
authors.initials: O
authors.lastname: Steeb
authors.affiliation: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Blane
authors.affiliation: Emerging Health Technologies, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Lia
authors.initials: L
authors.lastname: Rotherham
authors.affiliation: Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2050, South Africa.
authors.forename: Shaun
authors.initials: S
authors.lastname: Aron
authors.affiliation: Research Unit in Bioinformatics (RUBi), Department of Computer Science, Rhodes University, Grahamstown, South Africa.
authors.forename: Philip
authors.initials: P
authors.lastname: Machanick
authors.affiliation: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
authors.forename: Heini
authors.initials: H
authors.lastname: Dirr
authors.affiliation: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fanucchi
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D000072417:Protein Domains; D020349:Surface Plasmon Resonance
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D004247:DNA
keywords: DNA-protein interactions; FOXP2; binding affinity; sequence specificity; transcription factor