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The Antennapedia homeodomain protein from Drosophila melanogaster bound to a fragment of DNA (PDB ID 1AHD). The recognition helix and unstructured N-terminus are bound in the major and minor grooves respectively.

The homeodomain fold is a protein structural domain that binds DNA or RNA and is thus commonly found in transcription factors. The fold consists of a 60-amino acid helix-turn-helix structure in which three alpha helices are connected by short loop regions [1]. The N-terminal two helices 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. Homeodomain folds are found exclusively in eukaryotes but have high homology to lambda phage proteins that alter the expression of genes in prokaryotes. In eukaryotes, homeodomains induce cellular differentiation by initiating the cascades of coregulated genes required to produce individual tissues and organs.

Further information: Homeobox

Homeobox genes are stretches of DNA about 180 nucleotides long that code for homeodomain proteins in both vertebrates and invertebrates. The existence of homeoboxes was first discovered in Drosophila, where the radical alterations that resulted from mutations in homeobox genes were termed homeotic mutations. The most famous such mutation is Antennapedia, in which legs grow from the head of a fly instead of the expected antennae. Homeobox genes are thus critical in the establishment of body axes during embryogenesis.

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 bonds to the DNA backbone; 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'-ATTA-3'; sequence-independent binding occurs with significantly lower affinity.

Proteins containing a POU region consist of a homeodomain and a separate, structurally homologous POU domain that contains two helix-turn-helix motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with consensus sequence 5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. Interestingly, the POU domain itself has significant structural similarity with repressors expressed in bacteriophages, particularly lambda phage.

1. Branden C, Tooze J. (1999). Introduction to Protein Structure 2nd ed. Garland Publishing: New York, NY. (See especially pp159-66.)

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