Chemistry:CssII

From HandWiki
Centruroides suffusus suffusus β-toxin II
SCOP classification[1]
ClassSmall proteins
FoldKnottins (small inhibitors, toxins, lectins)
SuperfamilyScorpion toxin-like
FamilyLong-chain scorpion toxins
ProteinCssII
SpeciesCentruroides suffusus suffusus
UniProtP08900[2]

Centruroides suffusus suffusus toxin II (CssII) is a scorpion β-toxin from the venom of the scorpion Centruroides suffusus suffusus.[3] CssII primarily affects voltage-gated sodium channels by causing a hyperpolarizing shift of voltage dependence, a reduction in peak transient current, and the occurrence of resurgent currents.[4]

Sources

Centruroides suffusus suffusus is a Mexican scorpion from the genus Centruroides belonging to the family Buthidae. C. suffusus suffusus has at least seven different β-toxins, of which CssII is considered the major toxin in the venom affecting mammals.[5] The single gene for CssII has been identified, and cloned using E. coli, resulting in recombinant CssII.[6]

Chemistry

CssII is a single chain miniprotein, consisting of 66 amino acids:[7] 

Lys-Glu-Gly-Tyr-Leu-Val-Ser-Lys-Ser-Thr-Gly-Cys-Lys-Tyr-Glu-Cys-Leu-Lys-Leu-Gly-Asp-Asn-Asp-Tyr-Cys-Leu-Arg-Glu-Cys-Lys-Gln-Gln-Tyr-Gly-Lys-Ser-Ser-Gly-Gly-Tyr-Cys-Tyr-Ala-Phe-Ala-Cys-Trp-Cys-Thr-His-Leu-Tyr-Glu-Gln-Ala-Val-Val-Trp-Pro-Leu-Pro-Asn-Lys-Thr-Cys-Asn

It has four disulfide bridges and its scaffold is formed by a single α-helix, and a three-stranded β-sheet structure.[3] Typical for Css β-toxins, no methionine and isoleucine amino acids occur in the miniprotein. CssII’s characteristics include the replacement of proline in position 59 with tyrosine, differentiating it from all other α- and β-toxins. Moreover, glutamine (position 32) and histidine (position 57) replace lysine and glycine residues respectively, differentiating CssII from all other β-toxins. The protein is amidated at the C-terminal end.[7] CssII has been successfully produced in E.coli, resulting in a recombinant variant of CssII. rCssII is not amidated at the C-terminal, resulting in a slightly lower weight. Recombinant CssII was shown to exhibit similar toxicity as native CssII. However, His tagged CssII (HisrCssII) was shown to be less toxic to mice[6] [8]

Target

CssII targets voltage-gated sodium channels, and has the highest affinity for Nav1.6 channels.[4] CssII is thought to bind to a receptor site only accessible when the sodium channel is in its open state. Within this site Css toxin is hypothesized to bind to the residues of the IIS3-S4 loop, as well as the extracellular IIS4 end.[9] Nav1.6 channels are primarily expressed in the central nervous system, as well as the heart and glia cells.[10]

Mode of action

As CssII is a β-toxin, it binds to site 4 on the sodium channel, thus primarily affecting the voltage sensor domain of the channel.[9] It is thought that CssII binding to the voltage sensor domain is dependent on a conformational change of the sodium channel. The binding to site 4 induces a negative shift in voltage dependence, resulting in the aberrant opening of sodium channels. In addition, CssII reduces the peak transient current of the Nav1.6 channels, and causes the occurrence of resurgent currents in cells that otherwise would not exhibit this behavior. These effects might arise from different channel binding sites for CssII, as the effects on the resurgent current occur earlier than the left shift of activation, and the transient peak current reduction. However, these additional binding sites have not yet been defined.[4] Also, CssII might indirectly affects the reuptake of GABA. This interaction is thought to be due to a change in membrane potential which inhibits sodium dependent reuptake of GABA.[11]

Toxicity

The LD50 in mice is 25 μg/kg for subcutaneous injections, and .60 μg/kg for intracerebroventricular injections.[7] Bark scorpion venom is generally considered neurotoxic, and stings can be fatal. Buthidae stings are highly prevalent, especially in Mexico, with more than 200,000 stings annually.[12]

Treatment

C. suffusus suffusus can be treated by antivenom, such as Alacramyn. A non-toxic recombinant variant of CssII, that is able to displace native CssII, facilitates the production of specific antibodies that could protect against the C. suffusus suffusus sting.[8]

References

  1. ↑ "SCOPe 2.05: Domain d2li7a_: 2li7 A". scop.berkeley.edu. http://scop.berkeley.edu/sunid=242892. 
  2. ↑ "Beta-mammal toxin Css2 - Centruroides suffusus suffusus (Mexican scorpion)". uniprot.org. https://www.uniprot.org/uniprot/P08900. 
  3. ↑ 3.0 3.1 Saucedo, Alma L.; del Rio-Portilla, Federico; Picco, Cristiana; Estrada, Georgina; Prestipino, Gianfranco; Possani, Lourival D.; Delepierre, Muriel; Corzo, Gerardo (2012). "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): 478–487. doi:10.1016/j.bbapap.2012.01.003. ISSN 1570-9639. PMID 22251893. 
  4. ↑ 4.0 4.1 4.2 Schiavon, Emanuele; Pedraza-Escalona, Martha; Gurrola, Georgina B.; Olamendi-Portugal, Timoteo; Corzo, Gerardo; Wanke, Enzo; Possani, Lourival D. (2012). "Negative-shift activation, current reduction and resurgent currents induced by β-toxins from Centruroides scorpions in sodium channels". Toxicon 59 (2): 283–293. doi:10.1016/j.toxicon.2011.12.003. ISSN 0041-0101. PMID 22200496. 
  5. ↑ Jover, Emmanuel; Couraud, François; Rochat, Hervé (1980). "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): 1607–1614. doi:10.1016/S0006-291X(80)80082-9. ISSN 0006-291X. PMID 7417336. 
  6. ↑ 6.0 6.1 Estrada, Georgina; Garcia, Blanca I.; Schiavon, Emanuele; Ortiz, Ernesto; Cestele, Sandrine; Wanke, Enzo; Possani, Lourival D.; Corzo, Gerardo (2007). "Four disulfide-bridged scorpion beta neurotoxin CssII: Heterologous expression and proper folding in vitro". Biochimica et Biophysica Acta (BBA) - General Subjects 1770 (8): 1161–1168. doi:10.1016/j.bbagen.2007.04.006. ISSN 0304-4165. PMID 17544584. http://www.hal.inserm.fr/inserm-00378025/document. 
  7. ↑ 7.0 7.1 7.2 "Purification and chemical and biological characterizations of seven toxins from the Mexican scorpion, Centruroides suffusus suffusus". J. Biol. Chem. 262 (10): 4452–9. 1987. doi:10.1016/S0021-9258(18)61214-1. PMID 2435711. 
  8. ↑ 8.0 8.1 Hernández-Salgado, Kenya; Estrada, Georgina; Olvera, Alejandro; Coronas, Fredy I.; Possani, Lourival D.; Corzo, Gerardo (2009). "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): 93–99. doi:10.1016/j.imlet.2009.06.001. ISSN 0165-2478. PMID 19524619. 
  9. ↑ 9.0 9.1 Cestèle, Sandrine; Qu, Yusheng; Rogers, John C.; Rochat, Hervé; Scheuer, Todd; Catterall, William A. (1998). "Voltage Sensor–Trapping". Neuron 21 (4): 919–931. doi:10.1016/S0896-6273(00)80606-6. ISSN 0896-6273. PMID 9808476. 
  10. ↑ Catterall, William A (2000). "From Ionic Currents to Molecular Mechanisms". Neuron 26 (1): 13–25. doi:10.1016/S0896-6273(00)81133-2. ISSN 0896-6273. PMID 10798388. 
  11. ↑ Johnson, Tonny M; Quick, Michael W; Sakai, Ted T; Krishna, N.Rama (2000). "Expression of functional recombinant scorpion β-neurotoxin Css II in E. coli". Peptides 21 (6): 767–772. doi:10.1016/S0196-9781(00)00206-0. ISSN 0196-9781. PMID 10958995. 
  12. ↑ Chippaux, J.-P.; Goyffon, M. (2008). "Epidemiology of scorpionism: A global appraisal". Acta Tropica 107 (2): 71–79. doi:10.1016/j.actatropica.2008.05.021. ISSN 0001-706X. PMID 18579104. 



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