Beta-toxin Cll2, shortened to Cll2, is a toxin in the venom of the Mexican Scorpion species '' Centruroides limpidus limpidus''. The toxin belongs to the β-class family of sodium channel-inhibiting

scorpion toxins Scorpions are predatory arachnids of the order Scorpiones. They have eight legs, and are easily recognized by a pair of grasping pincers and a narrow, segmented tail, often carried in a characteristic forward curve over the back and always end ...

. It affects voltage-dependent activation, conductance and resurgent currents of voltage gated sodium channels by binding to site 4.

Etymology and Source

Cll2 is named after the venom produced by the species ''Centruroides limpidus limpidus'' (Cll, a Mexican scorpion).

Cll1 Toxin Cll1 is a toxin from the venom of the Mexican scorpion ''Centruroides limpidus limpidus'', which changes the activation threshold of sodium channels by binding to neurotoxin binding site 4, resulting in increased excitability. Etymology ...

and Cll2 are both derived from this venom. The ''Centruroides limpidus limpidus'' species is a member of the only genus that represents a life hazard to humans in Mexico, and is mainly found in the state of

Morelos Morelos (), officially the Free and Sovereign State of Morelos ( es, Estado Libre y Soberano de Morelos), is one of the 32 states which comprise the Federal Entities of Mexico. It is divided into 36 municipalities and its capital city is Cuer ...

Chemistry

Cll2 belongs to the beta-type of sodium channel-inhibiting scorpion toxins. The Cll venom consists of six fractions, of which only Cll2 is lethal, amounting to ~42% of the venom. Cll2 consists of thirteen sub-fractions, of which sub-fraction 9 is the largest. The molecular weight of Cll2 is about 7600 Da. The primary structure of the Cll2 toxin (toxin II.9) is:

Target

Like other scorpion beta toxins (beta-ScTxs), Cll2 targets

voltage-gated sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

s (VGSCs). It specifically binds to and alters the Na_v1.6 channel, as well as, but to a lesser extent, other Nav isoforms. It binds to the extracellular end of the ISS4 (loop between the third and fourth segment) voltage sensor and locks it in the activated outward position. This binding location is commonly referred to as VGSC site 4.

Mode of Action

Cll2 binding to the ISS4 shifts the voltage dependence of activation to more negative values. In addition, Cll2 shows a blocking effect on the peak transient current and it can increase the resurgent current in the Na_v 1.6 isoform. The toxin can induce a resurgent current in Na_v1.1 and to a lesser extent in the Na_v1.2 and Na_v1.4 isoforms. Cll2 has slight differences compared to

in its mode of action. Cll2 caused a current reduction in Na_v1.6 and to a lesser extent in Na_v 1.1, Na_v 1.4 and Na_v 1.5. Cll1, on the other hand, influences the channels Na_v 1.1 to Na_v 1.6 all in an equal way.

Toxicity

The

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...

for Cll is 3.30 mg/kg. The Cll venom consists of six components, of which only Cll2 is lethal. Cll 2 consists of thirteen sub-fractions, of which sub-fraction 9-13 are toxic. Sub-fraction 13 is only toxic to crustaceans (sweet water shrimps).

Treatment

The single chain variable antibody fragment (scFv) ER-5 was recently created by mutating earlier used scFVs which were used against other Mexican scorpion toxins. This scFv ER-5 was found to have a neutralizing effect on both Cll1 and Cll2.

References

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External links

*https://www.uniprot.org/taxonomy/6876 Neurotoxins Scorpion toxins Ion channel toxins