The DM (Doublesex/Mab-3) domain is found in proteins from worm to mammals. Null mutation in DM domain containing proteins doublesex and mab-3 are associated with intersexual phenotypes. These proteins are believed to function as transcription factors on downstream sex-determination genes, especially on neuroblast differenciation and yolk protein genes transcription [1,2].

The DM domain binds DNA as a dimer, allowing the recognition of pseudopalindromic sequences [3,4,5]. The NMR analysis of the DSX DM domain [5] revealed a novel zinc module containing 'intertwined' CCHC and HCCC zinc-binding sites. The recognition of the DNA requires the carboxy-terminal basic tail which contacts the minor groove of the target sequence.

The way the 'intertwined' motif is binding two atoms of zinc is illustrated in the following schematic representation:

                                            x x basic tail x x x Cter
                               x  x       x
                            x       H    C
                         x        x  \ /  x
                        x       x     Zn   x
  Nter x x x x x x x x x C x x C     / \  x
                       x  \  /      C x C
                       x   Zn      x
                        x / \    x
                         HxxxC x

'C': conserved cysteine involved in zinc binding.
'H': conserved histidine involved in zinc binding.
'Zn': zinc atom.

Some of the proteins containing a DM domain are listed below.

• Mammalian DRMT1 and DRMT2 proteins. They are candidates for SRY independent male to female sex reversal.
• Vertebrate TERRA proteins. Play specific roles in early somitogenesis of vertebrates.
• Drosophila doublesex (DSX) male and female specific isoforms. Each isoform is supposed to repress expression of terminal differentiation genes specific to the opposite sex. The male isoform binds the fbe enhancer of the yolk gene and prevent its expression [5].
• Caenorhabditis elegans Male-ABnormal-3 (Mab-3) protein. Expressed in males and repressed in hermaphrodites. Mutations affect the differentiation of certain tissues (intestine and lateral epidermis) in males but not in hermaphrodites.

As a signature pattern for the DM domain, we selected the six cysteines and the two histidines of the zinc module. We also developed a profile that covers the whole DM domain.