Beta-mammal toxin Cn2 explained

Cn2 toxin
Organism:Centruroides noxius
Pdb:1CN2
Uniprot:P01495

Beta-mammal toxin Cn2, also known as Cn2 toxin, is a single chain β-scorpion neurotoxic peptide and the primary toxin in the venom of the Centruroides noxius Hoffmann scorpion. The toxin specifically targets mammalian Nav1.6 voltage-gated sodium channels (VGSC).

Etymology and source

Cn2 is a neurotoxin named after and derived from the Centruroides noxius scorpion, which originates from and is endemic in the state of Nayarit, Western Mexico.[1] This scorpion produces a venom in which the Cn2 toxin is the most abundant component; it comprises approximately 6.8% of the scorpion venom.[2] [3] Cn2 toxin is one of the most noxious peptides against mammals.[2] Cn2 was initially purified and sequenced under the name of toxin II.9.2.2.[4] [5]

Chemistry

Scorpion toxins affecting the gating mechanisms of sodium channels are classically divided in two major classes: α- and β-scorpion toxins.[6] [7] However, many functional variations of these peptides have been demonstrated, with almost 10 different toxin subgroups that can be separately listed.[8] Cn2 is generally categorized as a β-scorpion toxin composed of a single chain polypeptide consisting of 66 amino acids,[2] [4] [9] [10]

The Cn2 toxin comprises a triple-stranded antiparallel β-sheet, a short α-helix, and four disulfide bridges.[11] Two of these disulfide bridges contribute to maintaining the relative position of one of the β-sheet and α-helix. The third disulfide bridge binds the long loop between the first β-sheet and α-helix to the C-terminus, while the fourth binds this loop to the third β-sheet. The Cn2 peptide contains many aromatic residues: seven tyrosine residues, two tryptophan residues and one phenylalanine residue.[11] These residues form two hydrophobic patches, a hydrophobic core, two positive patches, and a negative patch in the protein, which have been extensively described.[11]

Target

Cn2 specifically targets the mammalian voltage-gated sodium channel (VGSC) Nav1.6.

Mode of action

It is likely that Cn2 binds most strongly to the extracellular loop between the S3 and S4 segments when the channel is in depolarized state. CssIV, a β-toxin that shares 57 out of 66 amino acid residues with the Cn2 toxin according to NMR analysis,[12] mainly binds to the extracellular loop between the S3 and S4 segments within the second domain of the target voltage-gated sodium channel.[9] The activation curve of the channel shifts to more hyperpolarized potentials upon binding of the neurotoxin.[13] [14] Thus, only when a depolarizing pulse is applied before Cn2 administration, the current threshold of the target channels shifts from -30 mV to -60 mV in control versus 140 nM Cn2, respectively.[14] An explanation for this phenomenon is that the Cn2 toxin ‘traps’ the voltage sensor in activated position when it binds the extracellular loop in activated position,[13] [14] as has been hypothesized for β-toxins in general.[9] [15] The Cn2 toxin also produces a resurgent current and a reduction in peak inward current in the Nav1.6 channel. All these changes seem to increase the excitability of the neurons. However, in Purkinje cells Cn2 can induce an inactivation block in a stimulation paradigm that in control conditions induced regular firing.

Toxicity and treatment

Toxicity

Cn2 toxin is highly toxic to mammals[2] with a reported LD50 of 0.25-0.32 μg/20g mouse.[2] [16]

Treatment

Single-chain variable fragments (scFvs) have been used to recognize and neutralize Cn2 from Centruroides noxius venom. Specifically, scFv RU1 and LR have shown to complement each other, showing a better neutralization capacity when administered simultaneously.[17] These two scFvs have affinities in the picomolar range and remove most scorpion toxin poisoning symptoms. When administered as treatment for the Cn2 toxin, survival percentages range from 90-100%[18]

Notes and References

  1. Teruel R, Ponce-Saavedra J, Quijano-Ravell AF . Redescription of Centruroides noxius and description of a closely related new species from western Mexico (Scorpiones: Buthidae). . Revista Mexicana de Biodiversidad . 2015 . 86 . 4 . 896–911 . 10.1016/j.rmb.2015.09.010 . free .
  2. Zamudio F, Saavedra R, Martin BM, Gurrola-Briones G, Hérion P, Possani LD . Amino acid sequence and immunological characterization with monoclonal antibodies of two toxins from the venom of the scorpion Centruroides noxius Hoffmann . European Journal of Biochemistry . 204 . 1 . 281–92 . February 1992 . 1371253 . 10.1111/j.1432-1033.1992.tb16635.x .
  3. Valdivia HH, Martin BM, Ramírez AN, Fletcher PL, Possani LD . Isolation and pharmacological characterization of four novel Na+ channel-blocking toxins from the scorpion Centruroides noxius Hoffmann . Journal of Biochemistry . 116 . 6 . 1383–91 . December 1994 . 7706233 . 10.1093/oxfordjournals.jbchem.a124691 .
  4. Possani LD, Dent MA, Martin BM, Maelicke A, Svendsen I . The amino terminal sequence of several toxins from the venom of the Mexican scorpion Centruroides noxius Hoffmann. . Carlsberg Research Communications . 1981 . 46 . 4 . 207–214 . 10.1007/bf02906498 . free .
  5. Possani L, Steinmetz WE, Dent MA, Alagón AC, Wüthrich K . Preliminary spectroscopic characterization of six toxins from Latin American scorpions . Biochimica et Biophysica Acta (BBA) - Protein Structure . 669 . 2 . 183–92 . July 1981 . 7284435 . 10.1016/0005-2795(81)90239-7 .
  6. Jover E, Couraud F, Rochat H . Two types of scorpion neurotoxins characterized by their binding to two separate receptor sites on rat brain synaptosomes . Biochemical and Biophysical Research Communications . 95 . 4 . 1607–14 . August 1980 . 7417336 . 10.1016/S0006-291X(80)80082-9 .
  7. Wheeler KP, Watt DD, Lazdunski M . Classification of Na channel receptors specific for various scorpion toxins . Pflügers Archiv . 397 . 2 . 164–5 . April 1983 . 6306553 . 10.1007/BF00582058 . 21960134 .
  8. Possani LD, Becerril B, Delepierre M, Tytgat J . Scorpion toxins specific for Na+-channels . European Journal of Biochemistry . 264 . 2 . 287–300 . September 1999 . 10491073 . 10.1046/j.1432-1327.1999.00625.x . free .
  9. Cestèle S, Qu Y, Rogers JC, Rochat H, Scheuer T, Catterall WA . Voltage sensor-trapping: enhanced activation of sodium channels by beta-scorpion toxin bound to the S3-S4 loop in domain II . Neuron . 21 . 4 . 919–31 . October 1998 . 9808476 . 10.1016/S0896-6273(00)80606-6 . free .
  10. Vazquez A, Tapia JV, Eliason WK, Martin BM, Lebreton F, Delepierre M, Possani LD, Becerril B . Cloning and characterization of the cDNAs encoding Na+ channel-specific toxins 1 and 2 of the scorpion Centruroides noxius Hoffmann . Toxicon . 33 . 9 . 1161–70 . September 1995 . 8585086 . 10.1016/0041-0101(95)00058-T .
  11. Pintar A, Possani LD, Delepierre M . Solution structure of toxin 2 from centruroides noxius Hoffmann, a beta-scorpion neurotoxin acting on sodium channels . Journal of Molecular Biology . 287 . 2 . 359–67 . March 1999 . 10080898 . 10.1006/jmbi.1999.2611 .
  12. Saucedo AL, del Rio-Portilla F, Picco C, Estrada G, Prestipino G, Possani LD, Delepierre M, Corzo G . Solution structure of native and recombinant expressed toxin CssII from the venom of the scorpion Centruroides suffusus suffusus, and their effects on Nav1.5 sodium channels . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1824 . 3 . 478–87 . March 2012 . 22251893 . 10.1016/j.bbapap.2012.01.003 .
  13. Schiavon E, Pedraza-Escalona M, Gurrola GB, Olamendi-Portugal T, Corzo G, Wanke E, Possani LD . Negative-shift activation, current reduction and resurgent currents induced by β-toxins from Centruroides scorpions in sodium channels . Toxicon . 59 . 2 . 283–93 . February 2012 . 22200496 . 10.1016/j.toxicon.2011.12.003 .
  14. Schiavon E, Sacco T, Cassulini RR, Gurrola G, Tempia F, Possani LD, Wanke E . Resurgent current and voltage sensor trapping enhanced activation by a beta-scorpion toxin solely in Nav1.6 channel. Significance in mice Purkinje neurons . The Journal of Biological Chemistry . 281 . 29 . 20326–37 . July 2006 . 16702217 . 10.1074/jbc.M600565200 . free .
  15. Catterall WA, Cestèle S, Yarov-Yarovoy V, Yu FH, Konoki K, Scheuer T . Voltage-gated ion channels and gating modifier toxins . Toxicon . 49 . 2 . 124–41 . February 2007 . 17239913 . 10.1016/j.toxicon.2006.09.022 .
  16. Hernández-Salgado K, Estrada G, Olvera A, Coronas FI, Possani LD, Corzo G . Heterologous expressed toxic and non-toxic peptide variants of toxin CssII are capable to produce neutralizing antibodies against the venom of the scorpion Centruroides suffusus suffusus . Immunology Letters . 125 . 2 . 93–9 . August 2009 . 19524619 . 10.1016/j.imlet.2009.06.001 . free .
  17. Riaño-Umbarila L, Ledezma-Candanoza LM, Serrano-Posada H, Fernández-Taboada G, Olamendi-Portugal T, Rojas-Trejo S, Gómez-Ramírez IV, Rudiño-Piñera E, Possani LD, Becerril B . Optimal Neutralization of Centruroides noxius Venom Is Understood through a Structural Complex between Two Antibody Fragments and the Cn2 Toxin . The Journal of Biological Chemistry . 291 . 4 . 1619–30 . January 2016 . 26589800 . 10.1074/jbc.M115.685297 . 4722445 . free .
  18. Riaño-Umbarila L, Contreras-Ferrat G, Olamendi-Portugal T, Morelos-Juárez C, Corzo G, Possani LD, Becerril B . Exploiting cross-reactivity to neutralize two different scorpion venoms with one single chain antibody fragment . The Journal of Biological Chemistry . 286 . 8 . 6143–51 . February 2011 . 21156801 . 10.1074/jbc.M110.189175 . 3057807 . free .

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