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 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). This family includes metalo-endoproteases (TC#8.B.14.2).
References:
Braud, S., P. Belin, J. Dassa, L. Pardo, G. Mourier, A. Caruana, B.T. Priest, P. Dulski, M.L. Garcia, A. Ménez, J.C. Boulain, and S. Gasparini. (2004). BgK, a disulfide-containing sea anemone toxin blocking K⁺ channels, can be produced in Escherichia coli cytoplasm as a functional tagged protein. Protein Expr Purif 38: 69-78.
Costa, E.T., G.F. Barnabé, M. Li, A.A. Dias, T.R. Machado, P.F. Asprino, F.P. Cavalher, E.N. Ferreira, M. Del Mar Inda, M.H. Nagai, B. Malnic, M.L. Duarte, K.R. Leite, A.C. de Barros, D.M. Carraro, R. Chammas, H.A. Armelin, W. Cavenee, F. Furnari, and A.A. Camargo. (2015). Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals. Oncogene 34: 1270-1279.
Jouiaei, M., K. Sunagar, A. Federman Gross, H. Scheib, P.F. Alewood, Y. Moran, and B.G. Fry. (2015). Evolution of an ancient venom: recognition of a novel family of cnidarian toxins and the common evolutionary origin of sodium and potassium neurotoxins in sea anemone. Mol Biol Evol 32: 1598-1610.
Kolesova, Y.S., Y.Y. Stroylova, E.E. Maleeva, A.M. Moysenovich, D.V. Pozdyshev, V.I. Muronetz, and Y.A. Andreev. (2023). Modulation of TRPV1 and TRPA1 Channels Function by Sea Anemones'' Peptides Enhances the Viability of SH-SY5Y Cell Model of Parkinson''s Disease. Int J Mol Sci 25:.
Lancaster, E., E. Burnor, J. Zhang, and E. Lancaster. (2019). ADAM23 is a negative regulator of K1.1/K1.4 potassium currents. Neurosci Lett 704: 159-163. [Epub: Ahead of Print]
Menny, A., M.V. Lukassen, E.C. Couves, V. Franc, A.J.R. Heck, and D. Bubeck. (2021). Structural basis of soluble membrane attack complex packaging for clearance. Nat Commun 12: 6086.
Minagawa, S., M. Ishida, Y. Nagashima, and K. Shiomi. (1998). Primary structure of a potassium channel toxin from the sea anemone Actinia equina. FEBS Lett. 427: 149-151.
Ohnishi, J., E. Ohnishi, M. Jin, W. Hirano, D. Nakane, H. Matsui, A. Kimura, H. Sawa, K. Nakayama, H. Shibuya, K. Nagashima, and T. Takahashi. (2001). Cloning and characterization of a rat ortholog of MMP-23 (matrix metalloproteinase-23), a unique type of membrane-anchored matrix metalloproteinase and conditioned switching of its expression during the ovarian follicular development. Mol Endocrinol 15: 747-764.
Planchon, D., E. Rios Morris, M. Genest, F. Comunale, S. Vacher, I. Bièche, E.V. Denisov, L.A. Tashireva, V.M. Perelmuter, S. Linder, P. Chavrier, S. Bodin, and C. Gauthier-Rouvière. (2018). MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins. J Cell Sci 131:.
Rangaraju, S., K.K. Khoo, Z.P. Feng, G. Crossley, D. Nugent, I. Khaytin, V. Chi, C. Pham, P. Calabresi, M.W. Pennington, R.S. Norton, and K.G. Chandy. (2010). Potassium channel modulation by a toxin domain in matrix metalloprotease 23. J. Biol. Chem. 285: 9124-9136.
Examples:
TC#	Name	Organismal Type	Example
8.B.14.1.1	*Sea anemone Class 1 toxin, BgK of 37 aas It blocks channels containing Kv1 subunits; the 3-d structure is known (1BGKA) (Aneiros et al.* 1993). See also Kolesova et al. 2023**	Metazoa	Bgk of Bunodosoma granuliferum (Red warty sea anemone)

8.B.14.1.2	ShK potassium channel toxin (3-d structure known (1BEI; 1C2U_A))	Animals	*ShK Toxin of Stoichactis helianthus* (P29187)**

8.B.14.1.3	*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)**

8.B.14.1.4	Uncharacterized protein of 99 aas.	Animals (worms)	*UP of Ascaris suum* (Pig roundworm) (Ascaris lumbricoides)**

8.B.14.1.5	ShTK domain protein of 106 aas.	Animals (worms)	*ShTK domain protein of Necator americanus* (Human hookworm)**

8.B.14.1.6	*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)

Examples:
TC#	Name	Organismal Type	Example
8.B.14.2.1	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).	Mammals	*MMP23 of Mus musculus* (O88676)**

8.B.14.2.2	Matrix metalloproteinase-23, MMP23B, (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). ADAM22 and ADAM23 have opposite effects on K_v1.1/K_v1.4 currents, ADAM23 inhbiting and ADAM22 activating. The relative expression of these proteins may shape the expression of K⁺ currents in different neuronal membrane domains (Lancaster et al. 2019).		ADAM23 of Homo sapiens

8.B.14.2.3	Matrix metalloproteinase-14, MMP14 or MT1-MMP, of 582 aas and 2 TMSs at the N- and C-termini. It mediates extracellular matrix (ECM) degradation following targetting and endocytosis into endolysosomes in a flotillin (TC# 8.A.21.3.1)-dependent process. MMP14 promotes cancerous growth and metastasis (Planchon et al. 2018).		MMP14 of Homo sapiens

8.B.14.2.4	*Karilysin, Kly, of 472 aas and 1 N-terminal TMS. Karilysin appears to be a major virulence factor of T. forsythia* that contributes to evasion of the human immune response and periodontal disease.**		Kly of Tannerella forsythia (Bacteroides forsythus)

8.B.14.2.5	Vitronectin, VTN, of 478 aas. Vitronectin is a cell adhesion and spreading factor found in serum and tissues. It interacts with glycosaminoglycans and proteoglycans. It is recognized by certain members of the integrin family and serves as a cell-to-substrate adhesion molecule. It is also an inhibitor of the membrane-damaging effect of the terminal cytolytic complement pathway. It captures and clears soluble precursors of the membrane attack complex (sMAC) (Menny et al. 2021).		Vitronectin of Homo sapiens

Examples:
TC#	Name	Organismal Type	Example