Homeodomain (Hox) Transcription Factors Proteins

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Homeodomain (Hox) Transcription Factors Proteins

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Homeodomain (Hox) Transcription Factors Proteins Background

Members of the homeodomain (Hox) transcription factor family are characterized by the presence of a homology domain, which is a 60 amino acid helix-turn-helix DNA binding domain. A DNA sequence encoding a homologous domain is referred to as a "homology box" and a gene containing a homeobox is referred to as a "hox gene." The homeodomain is very highly conserved and consists of three helical regions that fold into a tight globular structure that binds to the 5'-TAAT-3' core motif. The recognition coil in the homologous domain binds to the DNA major groove, while the amino terminal tail contacts the DNA minor groove. Interestingly, homeodomains are also important for nucleoplasm transport of hox transcription factors. Members of the hox transcription factor family can function as monomers or homodimers to directly drive transcription of the target gene. The primary function of the hox transcription factor is to mimic the pre- and post-body axis of the embryo. More specifically, hox gene expression is critical for normal spatiotemporal limb and organ development.

Hox genes

The Hox gene is a group of related genes that determine the basic structure and direction of an organism. The Hox gene is critical for proper placement of the segmental structure of an animal during early embryonic development (eg, legs, antennae and wings in fruit flies or different vertebrate ribs in humans).

Hox genes are defined as having the following properties:

  • they encode protein with regulatory function such as transcription
  • they contain within them a DNA sequence known as the homeobox
  • most of them are linked together in a sequential cluster in the chromosome
  • they are organized on the sequential cluster in the order of their expression pattern along the cephalo-caudal (head to tail) axis of the organism.

Simple collinearity diagram. Figure 1. Simple collinearity diagram.

Hox proteins

Hox proteins are transcription factors because they bind to specific nucleotide sequences on DNA, called enhancers, which activate or inhibit genes. The same Hox protein acts as a repressor of one gene and as an activator of another gene. For example, in Drosophila melanogaster, the protein product of the Hox gene Antennapedia activates a gene designating a second thoracic segment that contains legs and wings and inhibits genes involved in eye and antenna formation. Therefore, no matter where the antenna protein is located, legs and wings are formed, but no eyes and tentacles are formed. The ability of a Hox protein to bind to DNA is conferred by a portion of the protein known as the homeodomain.


The characteristic homeodomain protein fold consists of a 60-amino acid long domain composed of three alpha helixes (Figure 2). Helix 2 and helix 3 form a so-called helix-turn-helix (HTH) structure (Figure 2), where the two alpha helices are connected by a short loop region.

The λ repressor of bacteriophage lambda employs two helix-turn-helix motifs (left; green) to bind DNA (right; blue and red). The λ repressor protein in this image is a dimer. Figure 2. The λ repressor of bacteriophage lambda employs two helix-turn-helix motifs (left; green) to bind DNA (right; blue and red). The λ repressor protein in this image is a dimer.

The N-terminal two helices of the homeodomain are antiparallel and the longer C-terminal helix is ​​roughly perpendicular to the axes established by the first two. It is this third helix that interacts directly with DNA via a number of hydrogen bonds and hydrophobic interactions, as well as indirect interactions via water molecules, which occur between specific side chains and the exposed bases within the major groove of the DNA. Homeodomain proteins are found in eukaryotes. Through the HTH motif, they share limited sequence Similarity and structural similarity to prokaryotic transcription factors, such as lambda phage proteins that alter the expression of genes in prokaryotes. The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins. One of the principal differences between HTH motifs in these different proteins arises from the stereo-chemical requirement for glycine in the turn which is needed to avoid steric interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, whereas for many of the homeotic and other DNA-binding proteins the requirement is relaxed.

 The consensus homeodomain (~60 amino acid residue chain).Figure 3. The consensus homeodomain (~60 amino acid residue chain).


1. Carroll S. B.; et al. Homeotic genes and the evolution of arthropods and chordates. Nature. 1995, 376 (6540): 479–485.

2. Fraser, P.; et al. Nuclear organization of the genome and the potential for gene regulation. Nature. 2007, 447 (7143): 413–7.

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