Structure of HoxA9 and Pbx1 bound to DNA: Hox hexapeptide and DNA recognition anterior to posterior.
By N. LaRonde-LeBlanc, C. Wolberger. 2003
206 citations recorded by the source corpus.
The HOX/HOM superfamily of homeodomain proteins controls cell fate and segmental embryonic patterning by a mechanism that is conserved in all metazoans. The linear arrangement of the Hox genes on the chromosome correlates with the spatial distribution of HOX protein expression along the anterior-posterior axis of the embryo. Most HOX proteins bind DNA cooperatively with members of the PBC family of TALE-type homeodomain proteins, which includes human Pbx1. Cooperative DNA binding between HOX and PBC proteins requires a residue N-terminal to the HOX homeodomain termed the hexapeptide, which differs significantly in sequence between anterior- and posterior-regulating HOX proteins. We report here the 1.9-A-resolution structure of a posterior HOX protein, HoxA9, complexed with Pbx1 and DNA, which reveals that the posterior Hox hexapeptide adopts an altered conformation as compared with that seen in previously determined anterior HOX/PBC structures. The additional nonspecific interactions and altered DNA conformation in this structure account for the stronger DNA-binding affinity and altered specificity observed for posterior HOX proteins when compared with anterior HOX proteins. DNA-binding studies of wild-type and mutant HoxA9 and HoxB1 show residues in the N-terminal arm of the homeodomains are critical for proper DNA sequence recognition despite lack of direct contact by these residues to the DNA bases. These results help shed light on the mechanism of transcriptional regulation by HOX proteins and show how DNA-binding proteins may use indirect contacts to determine sequence specificity.
Subfields: Global and Planetary Change, Molecular Biology
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Citations in the corpus
- Structural Basis for Sequence Specific DNA Binding and Protein Dimerization of HOXA13 (2011, background): “Exposed residues on the C-terminal helix (I366, N370, V373, K377, K381) correspond to DNA binding residues in the structures of other homeodomain proteins, Hoxb1 [9], Pdx1 [15], antennapedia [16,17], engrailed [18,19], and Hoxa9 [20].”
- Functional specificity of a Hox protein mediated by the recognition of minor groove structure. (2007, unknown): “Further, although the Hox-Exd/Pbx ternary structures reveal how these proteins interact with each otherwhilebound toDNA, they failtoexplain theobserved sequence specificities of Hox-Exd/Pbx dimers ( LaRonde-LeBlanc and Wolberger, 2003; Passner et al., 1999; Piper et al., 1999).”