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) | |||||||
|---|---|---|---|---|---|---|---|
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| Symbol | N/A | ||||||
| UniProt | 6876 | ||||||
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Etymology and Source
editCll2 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
editCll2 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
editLike other scorpion beta toxins (beta-ScTxs), Cll2 targets voltage-gated sodium channels (VGSCs). It specifically binds to and alters the Nav1.6 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
editCll2 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 Nav 1.6 isoform. The toxin can induce a resurgent current in Nav1.1 and to a lesser extent in the Nav1.2 and Nav1.4 isoforms.
Cll2 has slight differences compared to Cll1 in its mode of action. Cll2 caused a current reduction in Nav1.6 and to a lesser extent in Nav 1.1, Nav 1.4 and Nav 1.5. Cll1, on the other hand, influences the channels Nav 1.1 to Nav 1.6 all in an equal way.[3][5]
Toxicity
editThe 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
editThe 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]
References
edit- ^ Dehesa-Dávila M, Ramírez AN, Zamudio FZ, Gurrola-Briones G, Liévano A, Darszon A, Possani LD (February 1996). "Structural and functional comparison of toxins from the venom of the scorpions Centruroides infamatus infamatus, Centruroides limpidus limpidus and Centruroides noxius". Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 113 (2): 331–9. doi:10.1016/0305-0491(95)02031-4. PMID 8653586.
- ^ "Centruroides limpidus (Mexican scorpion) (Centruroides limpidus limpidus)". www.uniprot.org. Retrieved 2018-10-08.
- ^ a b c Schiavon E, Pedraza-Escalona M, Gurrola GB, Olamendi-Portugal T, Corzo G, Wanke E, Possani LD (February 2012). "Negative-shift activation, current reduction and resurgent currents induced by β-toxins from Centruroides scorpions in sodium channels". Toxicon. 59 (2): 283–93. doi:10.1016/j.toxicon.2011.12.003. PMID 22200496.
- ^ Catterall WA, Cestèle S, Yarov-Yarovoy V, Yu FH, Konoki K, Scheuer T (February 2007). "Voltage-gated ion channels and gating modifier toxins" (PDF). Toxicon. 49 (2): 124–41. doi:10.1016/j.toxicon.2006.09.022. PMID 17239913.
- ^ a b c Alagón AC, Guzmán HS, Martin BM, Ramírez AN, Carbone E, Possani LD (January 1988). "Isolation and characterization of two toxins from the Mexican scorpion Centruroides limpidus limpidus Karsch". Comparative Biochemistry and Physiology. B, Comparative Biochemistry. 89 (1): 153–61. doi:10.1016/0305-0491(88)90277-5. PMID 2451580.
- ^ Rodríguez-Rodríguez ER, Olamendi-Portugal T, Serrano-Posada H, Arredondo-López JN, Gómez-Ramírez I, Fernández-Taboada G, Possani LD, Anguiano-Vega GA, Riaño-Umbarila L, Becerril B (September 2016). "Broadening the neutralizing capacity of a family of antibody fragments against different toxins from Mexican scorpions". Toxicon. 119: 52–63. doi:10.1016/j.toxicon.2016.05.011. PMID 27212628.