Editing Homeobox (section)

== Homeodomain structure ==
The characteristic homeodomain [[protein fold]] consists of a 60-[[amino acid]] long domain composed of three [[alpha helix|alpha helices]]. The following shows the [[Consensus sequence|consensus]] homeodomain (~60 amino acid chain):<ref name="urlwww.csb.ki.se">{{cite web|url=http://www.csb.ki.se/groups/tbu/homeo/consensus.gif|title=The homeobox page|author=Bürglin TR|publisher=Karolinksa Institute|format=gif|access-date=2010-01-30|archive-date=2011-07-21|archive-url=https://web.archive.org/web/20110721024016/http://www.csb.ki.se/groups/tbu/homeo/consensus.gif|url-status=live}}</ref>

<pre>            Helix 1          Helix 2         Helix 3/4
         ______________    __________    _________________
RRRKRTAYTRYQLLELEKEFHFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
....|....|....|....|....|....|....|....|....|....|....|....|
         10        20        30        40        50        60</pre>
[[File:1NK2-NK2 homeodomain DNA complex.png|thumb|The vnd/NK-2 homeodomain-DNA complex. Helix 3 of the homeodomain binds in the major groove of the DNA and the N-terminal arm binds in the minor groove, in analogy with other homeodomain-DNA complexes.]]
Helix 2 and helix 3 form a so-called [[helix-turn-helix]] (HTH) structure, where the two alpha helices are connected by a short loop region. The [[N-terminus|N-terminal]] two helices of the homeodomain are [[Antiparallel (biochemistry)|antiparallel]] and the longer [[C-terminus|C-terminal]] helix is roughly perpendicular to the axes of 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 chain]]s and the exposed [[nucleotide|base]]s within the [[major groove]] of the DNA.<ref name="PUB00005540" />

Homeodomain proteins are found in [[eukaryote]]s.<ref name="pmid26464018"/> Through the HTH motif, they share limited sequence similarity and structural similarity to  prokaryotic transcription factors,<ref>{{cite web|url=http://www.cathdb.info/version/v4_0_0/superfamily/1.10.10.60|title=CATH Superfamily 1.10.10.60|website=www.cathdb.info|access-date=27 March 2018|archive-date=9 August 2017|archive-url=https://web.archive.org/web/20170809211333/http://www.cathdb.info/version/v4_0_0/superfamily/1.10.10.60|url-status=dead}}</ref> such as [[lambda phage]] proteins that alter the expression of genes in [[prokaryote]]s. The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g., [[Lambda phage#Protein function overview|cro]] and [[repressor protein]]s, homeodomain proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereochemical 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.

===Sequence specificity===

Homeodomains can bind both specifically and nonspecifically to [[B-DNA]] with the C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in the minor groove. The recognition helix and the inter-helix loops are rich in [[arginine]] and [[lysine]] residues, which form [[hydrogen bond]]s to the DNA backbone. [[conservation (genetics)|Conserved]] [[hydrophobic]] residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-TAAT-3'; sequence-independent binding occurs with significantly lower affinity. The specificity of a single homeodomain protein is usually not enough to recognize specific target gene promoters, making cofactor binding an important mechanism for controlling binding sequence specificity and target gene expression. To achieve higher target specificity, homeodomain proteins form complexes with other transcription factors to recognize the [[promoter (biology)|promoter region]] of a specific target gene.