8.B.19 The Sea Anemone K+ Channel Blocker Toxin, BcsTx3 (BcsTx3) Family

Sea anemone venoms are a rich source of peptide toxins which provide tools for studying the structures and functions of ion channels.  BcsTx3, a toxin found in the venom of a Bunodosoma caissarum (from Brazil) has been purified and biochemically and pharmacologically characterized (Orts et al. 2013). The pharmacological effects were studied on 12 different subtypes of voltage-gated potassium channels (K(V)1.1-K(V)1.6; K(V)2.1; K(V)3.1; K(V)4.2; K(V)4.3; hERG and Shaker IR) and three cloned voltage-gated sodium channel isoforms (Na(V)1.2, Na(V)1.4 and BgNa(V)1.1), all expressed in Xenopus laevis oocytes. BcsTx3 showed a high affinity for Drosophila Shaker IR channels over rKv1.2, hKv1.3 and rKv1.6, and was not active on NaV channels. Biochemical characterization revealed that BcsTx3 is a 50 amino acid peptide crosslinked by four disulfide bridges, and sequence comparison allowed BcsTx3 to be classified as a novel type of sea anemone toxin acting on KV channels. Putative toxins homologous to BcsTx3 from two additional actiniarian species were identified (Orts et al. 2013). 

These sea anemone toxins (subfamily 1) are clearly related to spider toxins (subfamily 2), and families 8.B.6 and 8.B.19 seem to be related to each other as well as possibly to 1.C.52, 8.B.3 and 8.B.5.  These tentative possibilities need to be confirmed.  However 8.B.3 and 8.B.5 are for sure related.



This family belongs to the Huwentoxin Superfamily.

 

References:

Agwa, A.J., L.V. Blomster, D.J. Craik, G.F. King, and C.I. Schroeder. (2018). Efficient Enzymatic Ligation of Inhibitor Cystine Knot Spider Venom Peptides: Using Sortase A To Form Double-Knottins That Probe Voltage-Gated Sodium Channel Na1.7. Bioconjug Chem. [Epub: Ahead of Print]

Kuhn-Nentwig, L., I.M. Fedorova, B.P. Lüscher, L.S. Kopp, C. Trachsel, J. Schaller, X.L. Vu, T. Seebeck, K. Streitberger, W. Nentwig, E. Sigel, and L.G. Magazanik. (2012). A venom-derived neurotoxin, CsTx-1, from the spider Cupiennius salei exhibits cytolytic activities. J. Biol. Chem. 287: 25640-25649.

Orts, D.J., Y. Moran, C.T. Cologna, S. Peigneur, B. Madio, D. Praher, L. Quinton, E. De Pauw, J.E. Bicudo, J. Tytgat, and J.C. de Freitas. (2013). BcsTx3 is a founder of a novel sea anemone toxin family of potassium channel blocker. FEBS J. 280: 4839-4852.

Sachkova, M.Y., A.A. Slavokhotova, E.V. Grishin, and A.A. Vassilevski. (2014). Structure of the yellow sac spider Cheiracanthium punctorium genes provides clues to evolution of insecticidal two-domain knottin toxins. Insect Mol Biol 23: 527-538.

Schalle, J., U. Kämpfer, S. Schürch, L. Kuhn-Nentwig, S. Haeberli, and W. Nentwig. (2001). CSTX-9, a toxic peptide from the spider Cupiennius salei: amino acid sequence, disulphide bridge pattern and comparison with other spider toxins containing the cystine knot structure. Cell Mol Life Sci 58: 1538-1545.

Vassilevski, A.A., I.M. Fedorova, E.E. Maleeva, Y.V. Korolkova, S.S. Efimova, O.V. Samsonova, L.V. Schagina, A.V. Feofanov, L.G. Magazanik, and E.V. Grishin. (2010). Novel class of spider toxin: active principle from the yellow sac spider Cheiracanthium punctorium venom is a unique two-domain polypeptide. J. Biol. Chem. 285: 32293-32302.

Examples:

TC#NameOrganismal TypeExample
8.B.19.1.1

The mature K+ channel blocking toxin, BcsTx3 of 50 aas (Orts et al. 2013).

Animals (Sea anemones)

BcsTx3 of Bunodosoma caissarum

 
8.B.19.1.2

Putative pro-toxin of 190 aas

Animals (see anemones)

Toxin precursor of Nematostella vectensis

 
Examples:

TC#NameOrganismal TypeExample
8.B.19.2.1

U1-ctenitoxin Cs1a (CstX-7).  Blocks mammalian neuronal L-type (Cav1/CACNA1) high-voltage-activated calcium channels.  Causes paralysis in Drosophila. Its insecticidal activity is synergistically increased by potassium ions, M-ctenitoxin-Cs1a (P83619), omega-ctenitoxin-Cs1a (P81694), and U1-ctenitoxin-Cs2a (P83919).  Because of the disulfide knot strcuture, this neurotoxin is called a knottin (Schalle et al. 2001).

Animals (spiders)

CstX-7 of Cupiennius salei

 
8.B.19.2.2

Peptide toxin, Cs1a omega ctenitoxin, of 74 aas from multicomponent venom.  Contains a cystine knot structure and is therefore called a knottin (Kuhn-Nentwig et al. 2012). Double-knottin peptides from spider venom havebeen used to reveal aspects of the pharmacology of transmembrane channels (Agwa et al. 2018).

Animals (wandering spiders)

Cs1a toxin of Cupiennius salei

 
8.B.19.2.3

UT-Lycotoxin, Ls1t (LsTx-A35) of 107 aas.  The disulfide knot defines it as a knottin.  It is a member of the CsTx superfamily and the U1-lycotoxin family.  This protein is processed to the mature form.

Animals (spiders)

Ks1t of Lycosa (Aranea) singoriensis

 
8.B.19.2.4Ω Lsp-IA (47aas) Ca2+ channel inhibitorSpidersΩ Lsp-IA of Geolycosa sp. (P85079)
 
8.B.19.2.5

Latartoxin 1b of 86 aas.  It is further processed to the mature form.  Belongs to the CsTx superfamily.  The presence of disulfide through disulfide knot structually defines it as a 'knottin'.

Spiders

Latartoxin 1b of Lachesana tarabaevi

 
8.B.19.2.6

U2-Lycotoxin Ls1c of 105 aas; calcium channel impairing toxin.  Also called LsTxM3.

Animals

U2 Lycotoxin Ls1c of Lycosa singoriensis

 
8.B.19.2.7

DELTA-miturgitoxin-Cp1b of 183 aas and 1 N-terminal TMS.  It is a spider venom toxin that exhibits cytolytic activity by forming an α-helix across the membrane and is lethal to insect larvae (Vassilevski et al. 2010, Sachkova et al. 2014). It causes instant paralysis and death to larvae of the flesh fly (S. carnaria) at doses of 20 µg/g, and at doses of less than 10 µg/g, it causes reversible paralysis by causing stable and irreversible depolarization of fly muscle fibers while destabilizing the membrane  (Vassilevski et al. 2010).

Toxin of Cheiracanthium punctorium (Yellow sac spider)