8.B.14 The Sea Anemone Peptide Toxin, Class 1 (BgK) Family
Peptide cnidarian toxin families, including peptide neurotoxins (voltage-gated Na+ and K+ channel-targeting toxins: NaTxs and KTxs, respectively, pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins), and the newly discovered small cysteine-rich peptides (SCRiPs). These have been isolated from several species of sea anemones and shown to block currents through various potassium ion channels, particularly in excitable cells. The toxins can be grouped into four structural classes: type 1 with 35-37 amino acid residues and three disulphide bridges; type 2 with 58-59 residues and three disulphide bridges; type 3 with 41-42 residues and three disulphide bridges; and type 4 with 28 residues and two disulphide bridges (Castañeda & Harvey, 2009). Examples from the first class are BgK from Bunodosoma granulifera, ShK from Stichodactyla helianthus and AsKS (or kaliseptine) from Anemonia sulcata (now A. viridis). These interfere with binding of radiolabelled dendrotoxin to synaptosomal membranes and block currents through channels with various Kv1 subunits and also intermediate conductance K(Ca) channels. Toxins in the second class are homologous to Kunitz-type inhibitors of serine proteases; these toxins include kalicludines (AsKC 1-3) from A. sulcata and SHTXIII from S. haddoni; they block Kv1.2 channels. The third structural group (8.B.11) includes proteins from A. sulcata and Anthropleura elegantissima. Their pharmacological specificities differs: BDS-I and -II toxins block currents involving Kv3 subunits while APETx1 blocks ERG channels. The fourth group comprises the SHTX I and II toxins from S. haddoni. Their channel blocking specificity is not yet known, but they displace dendrotoxin binding from synaptosomal membranes (Castañeda & Harvey, 2009).
Sea anemone Class 1 toxin, BgK of 37 aas (blocks channels containing Kv1 subunits); the 3-d structure known (1BGKA) (Aneiros et al. 1993).
Bgk of Bunodosoma granuliferum (Red warty sea anemone)
ShK potassium channel toxin (3-d structure known (1BEI; 1C2U_A))
ShK Toxin of Stoichactis helianthus (P29187)
Sea anemone voltage-sensitive K+ channel inhibitor, Actitoxin Aeq1a; of 36 aas. Also bolcks α-dendrotoxin binding (Minagawa et al. 1998).
Animals (sea anemones)
ShKT of Actina equina Beadlet anemone)
Uncharacterized protein of 99 aas.
UP of Ascaris suum (Pig roundworm) (Ascaris lumbricoides)
ShTK domain protein of 106 aas.
ShTK domain protein of Necator americanus (Human hookworm)
K+ channel blocker of 74 aas (Jouiaei et al. 2015). Inhibits voltage-gated potassium channels (Kv1.2/KCNA2) and facilitates acetylcholine release at the avian neuromuscular junction.
Animals; sea anemones
Toxin of Heteractis magnifica (Magnificent sea anemone) (Radianthus magnifica)
Matrix metalloprotease 23 (MMP23), with a C-terminal K channel blocking Toxin Domain, TxD (residues 254 - 290; 37 aas). The NMR structure of the 37 aa toxin domain is available (2K72_A) (Rangaraju et al., 2010).
MMP23 of Mus musculus (O88676)
Matrix metalloproteinase-23, MMP23B, (or ADAM23, MMP21 or MMP22) of 390 aas. It regulates the surface expression of several potassium channels by retaining them in the endoplasmic reticulum (Ohnishi et al. 2001; Costa et al. 2015).
ADAM23 of Homo sapiens