Cll2

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

Beta-toxin Cll2 (Cll2)
Identifiers
Organism	Centruroides limpidus limpidus
Symbol	N/A
UniProt	6876
Search for Structures Swiss-model Domains InterPro

Etymology and Source

Cll2 is named after the venom produced by the species Centruroides limpidus limpidus (Cll, a Mexican scorpion). Cll1 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.^[1]

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: ^[2]

KEGYLVNHST

GCKYECFKLG

DNDYCLRECK

QQYGKGAGGY

CYAFGCWCNH

LYEQAVWPL

PKKTCN

Target

Like other scorpion beta toxins (beta-ScTxs), Cll2 targets voltage-gated sodium channels (VGSCs). It specifically binds to and alters the Na_v1.6 channel, as well as, but to a lesser extent, other Nav isoforms.^[3] 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.^[3] This binding location is commonly referred to as VGSC site 4.^[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 Cll1 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.^[3][5]

Toxicity

The LD50 for Cll is 3.30 mg/kg.^[5] 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).^[5]

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.^[6]