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Homeo box is highly conservative gene fragment coding peptide with high affinity to some DNA sequences. It play a key role in regulation of gene expression. The proteins encoded by such Hox genes are possible candidate as transcription factors believed to be involved in given positional cues to different cell types along different rudiments and body axes.
Homeobox-containing genes are defined by the presence of a characteristic 183 base pair DNA sequence (homeobox) coding for a relatively conserved 61 amino acid section of protein (homeodomain).
It is important to realize that homeodomain sequences are far from invariant; thus the recognition of a homeodomain within a protein sequence is not always straightforward. In practice, homeodomains are usually recognized by the presence of three potential alpha-helical regions, conservation of several invariant amino acid residues, and a higher level of sequence similarity to previously characterised homeodomains than to other protein sequences. The least variable regions are two potential alpha-helices in the C-terminal half of the domain, which are thought to be responsible for sequence specific DNA binding and subsequent regulation of target genes.
First identified in a series of Drosophila genes that regulate development, the homeodomain is a conserved sequence of 60 amino acids. Homeodomain-containing proteins have now been found in all eukariotes examined, ranging from yeast to man. The tertiary structure of the homeo domain, as first determined by solution NMR studies of the Antennapedia homeodomain from Drosophila, consists of three alfa-helices (1, 2, 3) and a flexible N-terminal arm.
The second and third helices of this compact three-helix domain are structurally similar to helix-turn-helix motif of the prokaryotic repressors. The studies showed that the homeodomain makes base contacts in both grooves, with helix 3 in the major groove of the DNA and the N-terminal arm in the adjacent minor groove. In addition, the X-ray crystal structure of the engrailed-DNA complex revealed an extensive set of side-chain contacts with the sugar-phosphate backbone. Now as minimum as three cases of HD-DNA interactions are detaily investigated. This is homeodomains of Drosophilian Antp-gene product
,
engrailed gene product
and Nk-2 gene product.
Homeobox-containing genes are defined by the presence of a characteristic 183 base pair DNA sequence (homeobox) coding for a relatively conserved 61 amino acid section of protein (homeodomain). Homeodomains are usually recognized by the presence of three potential alpha-helical regions, conservation of several invariant amino acid residues, and a higher level of sequence similarity to previously characterized homeodomains than to other protein sequences. The least variable regions are two potential alpha-helices in the C-terminal half of the domain, which are thought to be responsible for sequence specific DNA binding and subsequent regulation of target genes.
Competition for binding sites between homeodomain (HD) containing proteins could dramatically influence the action of HD proteins during embryo pattern formation. Each of the many known HD proteins is expressed in a complex pattern during embryogenesis. As a result of overlap of these patterns, binding sites are exposed to a mixture of HD proteins that varies in composition in a complex spatio-temporal fashion. As the outcome of binding competition will on the relative concentrations of the binding proteins, the enhancer activity of a site might also vary in detailed spatio-temporal pattern. Additionally, the outcome of competition depends on the relative affinity of each of the related binding sites might undergo transitions in accupancy at distinct relative concentrations of HD proteins and would consequently have a unique spatio-temporal program of activity.
A paradox in our understanding of homeodomain function is that these proteins act with a high degree of specificity in development that not easily explained by differences in DNA-binding specificity. A critical question, therefore, concerns how HD regulatory specificity is determined. One possible mechanism for the determination of the biological specificity of HDs invokes interactions with other regulatory proteins (Pomerantz et al., 1992). Gregor and co-workers (1990) have recently show that the adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. The mouse C2 protein, which shares both physical properties and DNA binding specifity with USF, has been described as a mixture of dimers and tetramers (Peterson & Calame, 1989). Homo- and heterodimerization occur among members of a family of TF that share a common dimerization domain. The dimerization of TFs generally brings about a change in transcriptional activity, often mediated by change in sequence specifity or degree of activation.
[Gaunt SJ; Blum M; De Robertis EM; Development 117: 769-78 (1993)]