Structure of the forkhead domain of FOXP2 bound to DNA

  • Stroud J
  • Wu Y
  • Bates D
 et al. 
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Abstract

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 Å 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. ©2006 Elsevier Ltd All rights reserved.

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Authors

  • James C. Stroud

  • Yongqing Wu

  • Darren L. Bates

  • Aidong Han

  • Katja Nowick

  • Svante Paabo

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