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Structure of the forkhead domain of FOXP2 bound to DNA.

Stroud JC, Wu Y, Bates DL, Han A, Nowick K, Paabo S, Tong H, Chen L
Structure 14 159-66 (2006)
Cited: 129 times
EuropePMC logo PMID: 16407075

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 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.

Reviews - 2a07 mentioned but not cited (3)

  1. Protein acrobatics in pairs--dimerization via domain swapping. Gronenborn AM. Curr Opin Struct Biol 19 39-49 (2009)
  2. Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression. Kim JH, Hwang J, Jung JH, Lee HJ, Lee DY, Kim SH. Mol Cancer 18 180 (2019)
  3. Toward a mechanistic understanding of DNA binding by forkhead transcription factors and its perturbation by pathogenic mutations. Dai S, Qu L, Li J, Chen Y. Nucleic Acids Res 49 10235-10249 (2021)

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Reviews citing this publication (23)

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