Structure of the forkhead domain of FOXP2 bound to DNA.
FOXP (FOXP1-4) is a newly defined subfamily of the forkhead box (FOX) transcription factors. A mutation in the FOXP2 forkhead domain cosegregates with a severe speech disorder, whereas several mutations in the FOXP3 forkhead domain are linked to the IPEX syndrome in human and a similar autoimmune phenotype in mice. Here we report a 1.9 A crystal structure of the forkhead domain of human FOXP2 bound to DNA. This structure allows us to revise the previously proposed DNA recognition mechanism and provide a unifying model of DNA binding for the FOX family of proteins. Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer, made possible by a strategic substitution of a highly conserved proline in conventional FOX proteins with alanine in the P subfamily. Disease-causing mutations in FOXP2 and FOXP3 map either to the DNA binding surface or the domain-swapping dimer interface, functionally corroborating the crystal structure.
Stroud
James C
JC
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Colorado 80309, USA.
Wu
Yongqing
Y
Bates
Darren L
DL
Han
Aidong
A
Nowick
Katja
K
Paabo
Svante
S
Tong
Harry
H
Chen
Lin
L
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D051858:Forkhead Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D004268:DNA-Binding Proteins; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors