A DNA-binding domain in eukaryotic transcription factors superfamily

The DNA-binding domain of certain eukaryotic transcription factors displays a distinctive helix-turn-helix (HTH) motif. The MafG basic region-leucine zipper (bZIP) protein and the C. elegans Skn-1 transcription factor share this HTH motif.

MafG is a member of the Maf family of proteins, which are a subgroup of bZIP proteins that function as transcriptional regulators of cellular differentiation. Mafs can form either homodimers, or heterodimers with other bZIP proteins through their leucine zipper domains. MafG proteins are small Mafs that lack a putative transactivation domain. The DNA-binding domain of MafG contains the conserved Maf extended homology region (EHR), which is not present in other bZIP proteins. The EHR together with the basic region are responsible for the DNA-binding specificity of Mafs.

Skn-1 is a transcription factor that specifies mesodermal development in C. elegans. Skn-1 and MafG share a conserved DNA-binding motif, however Skn-1 lacks the leucine zipper dimerisation domain that is found in all bZIP proteins. Skn-1 acts as a monomer.

The DNA-binding domains in MafG [11875518] and Skn-1 [9628487] share structural similarity, despite a sequence identity of only 25%. The domain fold consists of three (MafG) to four (Skn-1) helices, where the long C-terminal helix protrudes from the domain and binds to DNA. MafG lacks the N-terminal helix of Skn-1. A basic cluster of residues is present on the surface of the domain, which together with the amino acid sequence motif, NXXYAXXCR, forms a DNA-binding surface. MafG and Skn-1 may use a common DNA-binding mode. However, the involvement of helix 2 (H2) in DNA recognition differs between MafG and Skn-1, with two residues at the beginning of H2 in MafG contributing to the unique DNA-binding specificity of Mafs.