BgK, a 37-residue peptide toxin from the sea anemone Bunodosoma granulifera, and ShK, a 35-residue peptide toxin from the sea anemone Stichodactyla helianthus, are potent inhibitors of K(+) channels. There is a large superfamily of proteins that contains domains (referred to as ShKT domains) ressembling these two toxins. Many of these proteins are metallopeptidases, whereas others are prolyl-4-hydroxylases, tyrosinases (see <PDOC00398>), peroxidases (see <PDOC00394>), oxidoreductases, or proteins containing epidermal growth factor-like domains (see <PDOC00021>), thrombospondin-type repeats (see <PDOC50092>), or trypsin-like serine protease domains (see <PDOC00124>) [1]. The ShKT domain has also been called NC6 (nematode six-cysteine) domain [2], SXC (six-cysteine) domain [2,3,4,5] and ICR (ion channel regulator) [1,6]. The ShKT domain is short (36 to 42 amino acids), with six conserved cysteines and a number of other conserved residues. The fold adopted by the ShKT domain contains two nearly perpendicular stretches of helices, with no additional canonical secondary structures (see <PDB:1BGK>) [7]. The globular architecture of the ShKT domain is stabilized by three disulfides, one of them linking the two helices. In venomous creatures, the ShKT domain may have been modified to give rise to potent ion channel blockers, whereas the incorporation of this domain into plant oxidoreductases and prolyl hydroxylases and into worm astacin-like metalloproteases and trypsin-like serines protaeses produced enzymes with potential channel-modulatory activity.

Some proteins known to contain a ShKT domain are listed below:

• Carribean sea anemone ShK, a potassium channel toxin [1].
• Sea anemone BgK, a potassium channel toxin [7].
• Toxocara canis family of secreted mucins Tc-MUC-1 to -5, which are implicated in immune evasion. They combine two evolutionarily distinct modules, the mucin and ShkT domains [2,3].
• Some Caenorhabditis elegans astacin-like proteins (nematode astacins, NAS), metalloproteases [5].
• Vertebrate cysteine-rich secretory proteins (Crisp) (see <PDOC00772>) [6].
• Mammalian microfibrillar-associated protein 2 (MFAP2 or MAGP1), a matrix protein.
• Plant prolyl 4-hydroxylase.

The profile we developed covers the entire ShKT domain.