Volume 43 Issue 5
Sep.  2022
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Fu-Chu Yuan, Fu-De Sun, Lin Zhang, Biao Huang, Hai-Long An, Ming-Qiang Rong, Can-Wei Du. General mechanism of spider toxin family I acting on sodium channel Nav1.7. Zoological Research, 2022, 43(5): 886-896. doi: 10.24272/j.issn.2095-8137.2022.185
Citation: Fu-Chu Yuan, Fu-De Sun, Lin Zhang, Biao Huang, Hai-Long An, Ming-Qiang Rong, Can-Wei Du. General mechanism of spider toxin family I acting on sodium channel Nav1.7. Zoological Research, 2022, 43(5): 886-896. doi: 10.24272/j.issn.2095-8137.2022.185

General mechanism of spider toxin family I acting on sodium channel Nav1.7

doi: 10.24272/j.issn.2095-8137.2022.185
#Authors contributed equally to this work
Funds:  This work was supported by the National Natural Science Foundation of China (31971190), Science Fund for Distinguished Young Scholars of Hunan Province (2021JJ10035), Education Department of Hunan Province (19A321)
More Information
  • Corresponding author: E-mail: rongmq@hunnu.edu.cnducw2022@163.com
  • Received Date: 2022-07-08
  • Accepted Date: 2022-09-01
  • Published Online: 2022-09-02
  • Publish Date: 2022-09-18
  • Various peptide toxins in animal venom inhibit voltage-gated sodium ion channel Nav1.7, including Nav-targeting spider toxin (NaSpTx) Family I. Toxins in NaSpTx Family I share a similar structure, i.e., N-terminal, loops 1–4, and C-terminal. Here, we used Mu-theraphotoxin-Ca2a (Ca2a), a peptide isolated from Cyriopagopus albostriatus, as a template to investigate the general properties of toxins in NaSpTx Family I. The toxins interacted with the cell membrane prior to binding to Nav1.7 via similar hydrophobic residues. Residues in loop 1, loop 4, and the C-terminal primarily interacted with the S3–S4 linker of domain II, especially basic amino acids binding to E818. We also identified the critical role of loop 2 in Ca2a regarding its affinity to Nav1.7. Our results provide further evidence that NaSpTx Family I toxins share similar structures and mechanisms of binding to Nav1.7.
  • #Authors contributed equally to this work
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  • [1]
    Agwa AJ, Lawrence N, Deplazes E, Cheneval O, Chen RM, Craik DJ, et al. 2017. Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1859(5): 835–844.
    Ahuja S, Mukund S, Deng LB, Khakh K, Chang E, Ho H, et al. 2015. Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist. Science, 350(6267): aac5464. doi: 10.1126/science.aac5464
    Bosmans F, Rash L, Zhu SY, Diochot S, Lazdunski M, Escoubas P, et al. 2006. Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes. Molecular Pharmacology, 69(2): 419−429. doi: 10.1124/mol.105.015941
    Cardoso FC, Lewis RJ. 2019. Structure-function and therapeutic potential of spider venom-derived cysteine knot peptides targeting sodium channels. Frontiers in Pharmacology, 10: 366. doi: 10.3389/fphar.2019.00366
    Carstens BB, Clark RJ, Daly NL, Harvey PJ, Kaas Q, Craik DJ. 2011. Engineering of conotoxins for the treatment of pain. Current Pharmaceutical Design, 17(38): 4242−4253. doi: 10.2174/138161211798999401
    Chang NS, French RJ, Lipkind GM, Fozzard HA, Dudley S. 1998. Predominant interactions between μ-conotoxin Arg-13 and the skeletal muscle Na+ channel localized by mutant cycle analysis. Biochemistry, 37(13): 4407−4419. doi: 10.1021/bi9724927
    Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. 2006. An SCN9A channelopathy causes congenital inability to experience pain. Nature, 444(7121): 894−898. doi: 10.1038/nature05413
    Cummins TR, Dib-Hajj SD, Waxman SG. 2004. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. Journal of Neuroscience, 24(38): 8232−8236. doi: 10.1523/JNEUROSCI.2695-04.2004
    de Lera Ruiz M, Kraus RL. 2015. Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. Journal of Medicinal Chemistry, 58(18): 7093−7118. doi: 10.1021/jm501981g
    Dib-Hajj SD, Yang Y, Black JA, Waxman SG. 2013. The NaV1.7 sodium channel: from molecule to man. Nature Reviews Neuroscience, 14(1): 49−62. doi: 10.1038/nrn3404
    Du CW, Li JM, Shao ZC, Mwangi J, Xu RJ, Tian HW, et al. 2019. Centipede KCNQ inhibitor SsTx also targets KV1.3. Toxins (Basel), 11(2): 76.
    Faber CG, Hoeijmakers JGJ, Ahn HS, Cheng XY, Han CY, Choi JS, et al. 2012. Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology, 71(1): 26−39. doi: 10.1002/ana.22485
    Hayes F, Van Melderen L. 2011. Toxins-antitoxins: diversity, evolution and function. Critical Reviews in Biochemistry and Molecular Biology, 46(5): 386−408. doi: 10.3109/10409238.2011.600437
    Horovitz A. 1996. Double-mutant cycles: a powerful tool for analyzing protein structure and function. Folding and Design, 1(6): R121−R126. doi: 10.1016/S1359-0278(96)00056-9
    Kalia J, Milescu M, Salvatierra J, Wagner J, Klint JK, King GF, et al. 2015. From foe to friend: using animal toxins to investigate ion channel function. Journal of Molecular Biology, 427(1): 158−175. doi: 10.1016/j.jmb.2014.07.027
    Kalman K, Pennington MW, Lanigan MD, Nguyen A, Rauer H, Mahnir V, et al. 1998. ShK-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide. Journal of Biological Chemistry, 273(49): 32697−32707. doi: 10.1074/jbc.273.49.32697
    Klint JK, Senff S, Rupasinghe DB, Er SY, Herzig V, Nicholson GM, et al. 2012. Spider-venom peptides that target voltage-gated sodium channels: pharmacological tools and potential therapeutic leads. Toxicon, 60(4): 478−491. doi: 10.1016/j.toxicon.2012.04.337
    Klint JK, Smith JJ, Vetter I, Rupasinghe DB, Er SY, Senff S, et al. 2015. Seven novel modulators of the analgesic target NaV1.7 uncovered using a high-throughput venom-based discovery approach. British Journal of Pharmacology, 172(10): 2445−2458. doi: 10.1111/bph.13081
    Lawrence N, Wu B, Ligutti J, Cheneval O, Agwa AJ, Benfield AH, et al. 2019. Peptide-membrane interactions affect the inhibitory potency and selectivity of spider toxins ProTx-II and GpTx-1. ACS Chemical Biology, 14(1): 118−130. doi: 10.1021/acschembio.8b00989
    Li DL, Xiao YC, Xu X, Xiong X, Lu SY, Liu ZH, et al. 2004. Structure-activity relationships of hainantoxin-IV and structure determination of active and inactive sodium channel blockers. Journal of Biological Chemistry, 279(36): 37734−37740. doi: 10.1074/jbc.M405765200
    Liu ZH, Cai TF, Zhu Q, Deng MC, Li JY, Zhou X, et al. 2013. Structure and function of hainantoxin-III, a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels isolated from the Chinese bird spider Ornithoctonus hainana. Journal of Biological Chemistry, 288(28): 20392–20403.
    Luo L, Li BW, Wang S, Wu FM, Wang XC, Liang P, et al. 2018. Centipedes subdue giant prey by blocking KCNQ channels. Proceedings of the National Academy of Sciences of the United States of America, 115(7): 1646−1651. doi: 10.1073/pnas.1714760115
    Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH. 2007. The MARTINI force field: coarse grained model for biomolecular simulations. The Journal of Physical Chemistry B, 111(27): 7812−7824. doi: 10.1021/jp071097f
    McCormack K, Santos S, Chapman ML, Krafte DS, Marron BE, West CW, et al. 2013. Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. Proceedings of the National Academy of Sciences of the United States of America, 110(29): E2724−2732.
    Minassian NA, Gibbs A, Shih AY, Liu Y, Neff RA, Sutton SW, et al. 2013. Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin huwentoxin-IV (μ-TRTX-Hh2a). Journal of Biological Chemistry, 288(31): 22707−22720. doi: 10.1074/jbc.M113.461392
    Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, et al. 2012. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nature Communications, 3: 791. doi: 10.1038/ncomms1795
    Payandeh J, Gamal El-Din TM, Scheuer T, Zheng N, Catterall WA. 2012. Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature, 486(7401): 135−139. doi: 10.1038/nature11077
    Payandeh J, Scheuer T, Zheng N, Catterall WA. 2011. The crystal structure of a voltage-gated sodium channel. Nature, 475(7356): 353−358. doi: 10.1038/nature10238
    Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, et al. 2008. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Molecular Pharmacology, 74(5): 1476−1484. doi: 10.1124/mol.108.047670
    Shcherbatko A, Rossi A, Foletti D, Zhu GY, Bogin O, Casas MG, et al. 2016. Engineering highly potent and selective microproteins against Nav1.7 sodium channel for treatment of pain. Journal of Biological Chemistry, 291(27): 13974−13986. doi: 10.1074/jbc.M116.725978
    Shen HZ, Liu DL, Wu K, Lei JL, Yan N. 2019. Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins. Science, 363(6433): 1303−1308. doi: 10.1126/science.aaw2493
    Sun FD, Ding XF, Xu LD, Liang JF, Chen L, Luo SZ. 2017. A molecular dynamics study of the short-helical-cytolytic peptide assembling and bioactive on membrane interface. The Journal of Physical Chemistry C, 121(32): 17263−17275. doi: 10.1021/acs.jpcc.7b04347
    Sun FD, Schroer CFE, Palacios CR, Xu LD, Luo SZ, Marrink SJ. 2020. Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2. PLoS Computational Biology, 16(4): e1007777. doi: 10.1371/journal.pcbi.1007777
    Tang DF, Xu JH, Li YP, Zhao P, Kong XJ, Hu HL, et al. 2021. Molecular mechanisms of centipede toxin SsTx-4 inhibition of inwardly rectifying potassium channels. Journal of Biological Chemistry, 297(3): 101076. doi: 10.1016/j.jbc.2021.101076
    Thomas-Tran R, Du Bois J. 2016. Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNaV1.7. Proceedings of the National Academy of Sciences of the United States of America, 113(21): 5856−5861. doi: 10.1073/pnas.1603486113
    Weiss J, Pyrski M, Jacobi E, Bufe B, Willnecker V, Schick B, et al. 2011. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature, 472(7342): 186−190. doi: 10.1038/nature09975
    Wisedchaisri G, Tonggu L, El-Din TMG, McCord E, Zheng N, Catterall WA. 2021. Structural basis for high-affinity trapping of the NaV1.7 channel in its resting state by tarantula toxin. Molecular Cell, 81(1): 38−48.e4. doi: 10.1016/j.molcel.2020.10.039
    Xiao YC, Bingham JP, Zhu WG, Moczydlowski E, Liang SP, Cummins TR. 2008. Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration. Journal of Biological Chemistry, 283(40): 27300−27313. doi: 10.1074/jbc.M708447200
    Xiao YC, Blumenthal K, Jackson II JO, Liang SP, Cummins TR. 2010. The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. Molecular Pharmacology, 78(6): 1124−1134. doi: 10.1124/mol.110.066332
    Xu H, Li TB, Rohou A, Arthur CP, Tzakoniati F, Wong E, et al. 2019. Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin. Cell, 176(4): 702−715.e14. doi: 10.1016/j.cell.2018.12.018
    Yang SL, Xiao Y, Kang D, Liu J, Li Y, Undheim EAB, et al. 2013. Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models. Proceedings of the National Academy of Sciences of the United States of America, 110(43): 17534−17539. doi: 10.1073/pnas.1306285110
    Yu FH, Catterall WA. 2003. Overview of the voltage-gated sodium channel family. Genome Biology, 4(3): 207. doi: 10.1186/gb-2003-4-3-207
    Zhang Y. 2015. Why do we study animal toxins?. Zoological Research, 36(4): 183–222.
    Zhang YX, Peng DZ, Huang B, Yang QC, Zhang QF, Chen MZ, et al. 2018. Discovery of a novel Nav1.7 inhibitor from Cyriopagopus albostriatus venom with potent analgesic efficacy. Frontiers in Pharmacology, 9: 1158. doi: 10.3389/fphar.2018.01158
    Zhang YX, Wang L, Peng DZ, Zhang QF, Yang QC, Li JY, et al. 2021. Engineering of highly potent and selective HNTX-III mutant against hNav1.7 sodium channel for treatment of pain. Journal of Biological Chemistry, 296: 100326. doi: 10.1016/j.jbc.2021.100326
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