Wasabi receptor toxin

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Urodacus manicatus2.jpg
Australian black rock scorpion ( Urodacus manicatus ).
Wasabi Receptor Toxin (WaTx). [1]
Species Urodacus manicatus
Class Small protein
SuperfamilyShort scorpion toxin
FamilyPotassium channel inhibitor KTx
Subfamilykappa-KTx
ProteinWasabi Receptor Toxin
PDB 6OFA_A

Wasabi receptor toxin (WaTx) is the active component of the venom of the Australian black rock scorpion Urodacus manicatus . WaTx targets TRPA1, also known as the wasabi receptor or irritant receptor. WaTx is a cell-penetrating toxin that stabilizes the TRPA1 channel open state while reducing its Ca2+-permeability, thereby eliciting pain and pain hypersensitivity without the neurogenic inflammation that typically occurs in other animal toxins.

Contents

Etymology

This scorpion toxin was named WaTx because it targets TRPA1 in a similar fashion as plant-derived irritants, such as mustard oil and wasabi. [1] These irritants activate the TRPA1 channel in peripheral primary afferent sensory neurons, subsequently eliciting their pungent taste as well as sinus clearing and eye stinging. [2] [3]

Sources

WaTx originates from the venom of the Australian Black Rock Scorpion ( Urodacus manicatus ). [1]

Chemistry

Family

WaTx belongs to the κ-KTx family, as it shows similarities in the disulfide bonding pattern. [1] The KTx family is classified into four subfamilies: α-, β-, γ-, and κ-KTx. [4] Unlike other KTx subfamilies, κ-KTx scorpion toxins form cysteine-stabilized α-helical hairpins (Cs α/α), whereas κ-KTx spider and crab toxins form cysteine-stabilized antiparallel β-sheets (Cs β/β). [5] [6] [7]

Structure

WaTx is a macromolecule with an estimated weight of 3.86 kDa, [8] which consists of 33 amino-acid residues. [1] Its amino-acid sequence is as follows:

Ala-Ser-Pro-Gln-Gln-Ala-Lys-Tyr-Cys-Tyr-Glu-Gln-Cys-Asn-Val-Asn-Lys-Val-Pro-Phe-Asp-Gln-Cys-Tyr-Gln-Met-Cys-Ser-Pro-Leu-Glu-Arg-Ser (ASPQQAKYCYEQCNVNKVPFDQCYQMCSPLERS)

The pattern of cysteine residues in the amino acid sequence, which is underlined above, indicates an independent Cys9-Cys27, Cys13-Cys23 disulfide bonding pattern. The two disulfide bridges connect two parallel α-helices with a β-turn. [5] The disulfide bonding pattern stabilizes the rigid and compact helical hairpin structure at two points, contributing to the stable tertiary structure of the protein. [5]

The hairpin contains four basic residues that enable passive diffusion across the membrane. Two features of the protein structure have been associated with cell-penetrating properties that are uncommon for peptide toxins. Firstly, a patch (or predominance) of basic residues is located at the open end of the hairpin, where the amino- and carboxy-terminal meet. Secondly, the amino-terminal in WaTx exhibits a dense dipole moment. [1] Other proteins with the ability to penetrate the plasma membrane include HIV Tat and Drosophila penetratin. [9] [10] [11] However, these proteins have no sequence resemblance to WaTx. [1]

Homology

The amino-acid sequence of WaTx bears little resemblance to other peptides in terms of homology. [1] Although the toxin was discovered to be cell-penetrating, there is no sequence similarity to classical cell-penetrating peptides (CPPs). [12]

Target

WaTx targets TRPA1, [1] one of about 30 transient receptor potential channels. WaTx is both potent and selective for TRPA1. Other known TRP-channels are not activated by the toxin. WaTx has an effect on human TRPA1 (hTRPA1), while it does not have an effect on to rat and snake TRPA1 (rsTRPA1). [1]

Mode of action

WaTx penetrates the plasma membrane instead of following standard routes, subsequently accessing the inferior part of the cell. The basic residues and dipole moment on the helical hairpin structure enable the passive diffusion of WaTx. [1]

Once the toxin arrives in the cell, it activates TRPA1 via an intracellular domain in the lower part of voltage-sensing segments S1-S4 called ‘the allosteric nexus’. [1] The allosteric nexus is located at the region where the TRP-like domain, pre-S1 helix and cysteine-rich S4-S5 linker meet. [13] This inner cavity is a common binding site to reactive electrophilic ligands—and now WaTx. This locus is a key regulatory site for stimulus integration and propagates conformational changes to the channel's gate. When activated, the open-state TRPA1 allows the flow of positively charged sodium and calcium ions into the cell. [1]

Electrophilic ligands make covalent modifications to specific cysteine residues in the cytoplasmic amino-terminus that increase the probability of channel opening. [14] [15] [16] Although both Na+ and Ca2+ can enter TRPA1, the channel normally has a preference towards Ca2+ and the intracellular calcium concentration increases more rapidly than the sodium concentration. WaTx interacts differently with the channel compared to reactive electrophiles. WaTx non-covalently binds to the allosteric nexus and initiates interactions with an integrated complex between the N-terminal cysteine-rich linker (S4-S5) and C-terminal TRP-like domains. [1] This prevents the open channel from closing, as opposed to increasing the probability of opening, and results in a prolonged duration of the channel's open state. With WaTx bound in open state, TRPA1 lacks a preference for Ca2+ over Na+, which accounts for the lower calcium permeability. Consequently, both electrophilic ligands and WaTx trigger a pain response, but the calcium levels that result from WaTx are too low to initiate subsequent neuropeptide release and neurogenic inflammation. [1] [17] [18] This suggests that WaTx may act only to open the ion permeation gate of TRPA1, without dilating the selectivity filter (dilation of the selectivity filter having been proposed to underlie enhanced calcium permeability of TRPA1 after activation by classical electrophilic irritants). [17]

Toxicity

WaTx elicits acute thermal and mechanical hypersensitivity. This response has been proven phenotypically proven by injecting WaTx in the hind paw of mice, which leads to dose-dependent nocifensive behavior. However, WaTx does not cause the local edema that is typical for noxious electrophiles. This lack of swelling indicates that WaTx fails to promote the release of calcitonin gene-related peptide (CGRP)—a hallmark of neurogenic inflammation. [1]

Treatment

There is no immediate danger after being stung by an Australian Black Rock Scorpion. The wound should be washed and cleaned, after which medical advice should be sought. [19]

Therapeutic use

So far, there are no pharmacologicals based on (the mode of action of) WaTx. However, understanding the mechanisms of WaTx's interaction with TRPA1 may aid in the development of therapeutics targeting TRPA1, which is considered a promising target for treating pain, itch and neurogenic inflammation syndromes that involve nociception. [1] [20] [21] [22]

Related Research Articles

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<span class="mw-page-title-main">Double-knot toxin</span>

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References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Lin King, John V.; Emrick, Joshua J.; Kelly, Mark J.S.; Herzig, Volker; King, Glenn F.; Medzihradszky, Katalin F.; Julius, David (September 2019). "A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain". Cell. 178 (6): 1362–1374.e16. doi:10.1016/j.cell.2019.07.014. PMC   6731142 . PMID   31447178.
  2. ↑ Jordt, Sven-Eric; Bautista, Diana M.; Chuang, Huai-hu; McKemy, David D.; Zygmunt, Peter M.; Högestätt, Edward D.; Meng, Ian D.; Julius, David (January 2004). "Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1". Nature. 427 (6971): 260–265. Bibcode:2004Natur.427..260J. doi:10.1038/nature02282. ISSN   0028-0836. PMID   14712238. S2CID   4354737.
  3. ↑ Bandell, Michael; Story, Gina M; Hwang, Sun Wook; Viswanath, Veena; Eid, Samer R; Petrus, Matt J; Earley, Taryn J; Patapoutian, Ardem (March 2004). "Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin". Neuron. 41 (6): 849–857. doi: 10.1016/S0896-6273(04)00150-3 . PMID   15046718.
  4. ↑ Camargos, Thalita Soares; Restano-Cassulini, Rita; Possani, Lourival Domingos; Peigneur, Steve; Tytgat, Jan; Schwartz, Carlos Alberto; Alves, Erica Maria C; de Freitas, Sonia Maria; Schwartz, Elisabeth Ferroni (July 2007). "The new kappa-KTx 2.5 from the scorpion Opisthacanthus cayaporum". Peptides. 32 (7): 1509–1517. doi: 10.1016/j.peptides.2011.05.017 . PMID   21624408.
  5. 1 2 3 Quintero-Hernández, V.; Jiménez-Vargas, J.M.; Gurrola, G.B.; Valdivia, H.H.; Possani, L.D. (December 2013). "Scorpion venom components that affect ion-channels function". Toxicon. 76: 328–342. doi:10.1016/j.toxicon.2013.07.012. PMC   4089097 . PMID   23891887.
  6. ↑ Silva, Pedro I.; Daffre, Sirlei; Bulet, Philippe (27 October 2000). "Isolation and Characterization of Gomesin, an 18-Residue Cysteine-rich Defense Peptide from the Spider Acanthoscurria gomesiana Hemocytes with Sequence Similarities to Horseshoe Crab Antimicrobial Peptides of the Tachyplesin Family". Journal of Biological Chemistry. 275 (43): 33464–33470. doi: 10.1074/jbc.M001491200 . ISSN   0021-9258. PMID   10942757.
  7. ↑ Srinivasan, Kellathur N.; Sivaraja, Vaithiyalingam; Huys, Isabelle; Sasaki, Toru; Cheng, Betty; Kumar, Thallampuranam Krishnaswamy S.; Sato, Kazuki; Tytgat, Jan; Yu, Chin; San, B. Chia Cheng; Ranganathan, Shoba (16 August 2002). "κ-Hefutoxin1, a Novel Toxin from the Scorpion Heterometrus fulvipes with Unique Structure and Function: IMPORTANCE OF THE FUNCTIONAL DIAD IN POTASSIUM CHANNEL SELECTIVITY". Journal of Biological Chemistry. 277 (33): 30040–30047. doi: 10.1074/jbc.M111258200 . ISSN   0021-9258. PMID   12034709.
  8. ↑ "Protein Molecular Weight". www.bioinformatics.org. Retrieved 2019-10-05.
  9. ↑ Vivès, Eric; Brodin, Priscille; Lebleu, Bernard (1997-06-20). "A Truncated HIV-1 Tat Protein Basic Domain Rapidly Translocates through the Plasma Membrane and Accumulates in the Cell Nucleus". Journal of Biological Chemistry. 272 (25): 16010–16017. doi: 10.1074/jbc.272.25.16010 . ISSN   0021-9258. PMID   9188504.
  10. ↑ Frankel, Alan D.; Pabo, Carl O. (December 1988). "Cellular uptake of the tat protein from human immunodeficiency virus". Cell. 55 (6): 1189–1193. doi: 10.1016/0092-8674(88)90263-2 . PMID   2849510.
  11. ↑ Joliot, Alain; Prochiantz, Alain (March 2004). "Transduction peptides: from technology to physiology". Nature Cell Biology. 6 (3): 189–196. doi:10.1038/ncb0304-189. ISSN   1465-7392. PMID   15039791. S2CID   27242169.
  12. ↑ Guidotti, Giulia; Brambilla, Liliana; Rossi, Daniela (April 2017). "Cell-Penetrating Peptides: From Basic Research to Clinics". Trends in Pharmacological Sciences. 38 (4): 406–424. doi:10.1016/j.tips.2017.01.003. PMID   28209404.
  13. ↑ Zimova, Lucie; Sinica, Viktor; Kadkova, Anna; Vyklicka, Lenka; Zima, Vlastimil; Barvik, Ivan; Vlachova, Viktorie (2018-01-23). "Intracellular cavity of sensor domain controls allosteric gating of TRPA1 channel". Science Signaling. 11 (514): eaan8621. doi: 10.1126/scisignal.aan8621 . ISSN   1945-0877. PMID   29363587.
  14. ↑ Bahia, Parmvir K.; Parks, Thomas A.; Stanford, Katherine R.; Mitchell, David A.; Varma, Sameer; Stevens, Stanley M.; Taylor-Clark, Thomas E. (June 2016). "The exceptionally high reactivity of Cys 621 is critical for electrophilic activation of the sensory nerve ion channel TRPA1". The Journal of General Physiology. 147 (6): 451–465. doi:10.1085/jgp.201611581. ISSN   0022-1295. PMC   4886278 . PMID   27241698.
  15. ↑ Hinman, A.; Chuang, H.-h.; Bautista, D. M.; Julius, D. (2006-12-19). "TRP channel activation by reversible covalent modification". Proceedings of the National Academy of Sciences. 103 (51): 19564–19568. Bibcode:2006PNAS..10319564H. doi: 10.1073/pnas.0609598103 . ISSN   0027-8424. PMC   1748265 . PMID   17164327.
  16. ↑ Macpherson, Lindsey J.; Dubin, Adrienne E.; Evans, Michael J.; Marr, Felix; Schultz, Peter G.; Cravatt, Benjamin F.; Patapoutian, Ardem (February 2002). "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines". Nature. 445 (7127): 541–545. doi:10.1038/nature05544. ISSN   0028-0836. PMID   17237762. S2CID   4344572.
  17. 1 2 Zhao, Jianhua; King, John V. Lin; Cheng, Yifan; Julius, David (2019-12-27). "Mechanisms governing irritant-evoked activation and calcium modulation of TRPA1". bioRxiv: 2019.12.26.888982. doi: 10.1101/2019.12.26.888982 .
  18. ↑ Zhao, Jianhua; Lin King, John V.; Paulsen, Candice E.; Cheng, Yifan; Julius, David (2020-07-08). "Irritant-evoked activation and calcium modulation of the TRPA1 receptor". Nature. 585 (7823): 141–145. Bibcode:2020Natur.585..141Z. doi:10.1038/s41586-020-2480-9. ISSN   0028-0836. PMC   7483980 . PMID   32641835.
  19. ↑ Isbister, Geoffrey K.; Volschenk, Erich S.; Balit, Corrine R.; Harvey, Mark S. (June 2003). "Australian scorpion stings: a prospective study of definite stings". Toxicon. 41 (7): 877–883. doi:10.1016/S0041-0101(03)00065-5. PMID   12782088.
  20. ↑ Julius, David (2013-10-06). "TRP Channels and Pain". Annual Review of Cell and Developmental Biology. 29 (1): 355–384. doi:10.1146/annurev-cellbio-101011-155833. ISSN   1081-0706. PMID   24099085. S2CID   32380825.
  21. ↑ Bautista, Diana M.; Jordt, Sven-Eric; Nikai, Tetsuro; Tsuruda, Pamela R.; Read, Andrew J.; Poblete, Jeannie; Yamoah, Ebenezer N.; Basbaum, Allan I.; Julius, David (March 2006). "TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents". Cell. 124 (6): 1269–1282. doi: 10.1016/j.cell.2006.02.023 . PMID   16564016.
  22. ↑ Andersson, D. A.; Gentry, C.; Moss, S.; Bevan, S. (2008-03-05). "Transient Receptor Potential A1 Is a Sensory Receptor for Multiple Products of Oxidative Stress". Journal of Neuroscience. 28 (10): 2485–2494. doi:10.1523/JNEUROSCI.5369-07.2008. ISSN   0270-6474. PMC   2709206 . PMID   18322093.
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