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PDBsum entry 2a07
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Transcription/DNA
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PDB id
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2a07
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References listed in PDB file
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Key reference
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Title
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Structure of the forkhead domain of foxp2 bound to DNA.
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Authors
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J.C.Stroud,
Y.Wu,
D.L.Bates,
A.Han,
K.Nowick,
S.Paabo,
H.Tong,
L.Chen.
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Ref.
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Structure, 2006,
14,
159-166.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 6.
Figure 6. Disease Mutations
(A) IPEX mutation
Ile363Val in FOXP3. The corresponding residue in FOXP2, Ile530,
forms a cascade of van der Waals interactions with Leu527,
Leu556, and Trp573 that contribute directly or indirectly to DNA
binding.
(B) IPEX mutation Ala384Thr in FOXP3. The
corresponding residue Ala551 in FOXP2 on helix H3 packs
intimately against Tyr509. The Ala384Thr mutation would bring an
extra g-methyl group into a tightly packed protein/DNA interface
and disrupt DNA binding.
(C) IPEX mutations Phe371Cys and
Phe371Leu in FOXP3. The corresponding residue Phe538 in FOXP2 is
critically located at the center of the domain-swapped dimer
interface. Mutations of this phenylalanine residue to Cys or
even a hydrophobic residue Leu may disrupt dimerization.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2006,
14,
159-166)
copyright 2006.
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