Molecular Diversity

, Volume 10, Issue 4, pp 545–554

Molecular diversification in spider venoms: A web of combinatorial peptide libraries

Review

Summary

Spider venoms are a rich source of novel pharmacologically and agrochemically interesting compounds that have received increased attention from pharmacologists and biochemists in recent years. The application of technologies derived from genomics and proteomics have led to the discovery of the enormous molecular diversity of those venoms, which consist mainly of peptides and proteins. The molecular diversity of spider peptides has been revealed by mass spectrometry and appears to be based on a limited set of structural scaffolds. Genetic analysis has led to a further understanding of the molecular evolution mechanisms presiding over the generation of these combinatorial peptide libraries. Gene duplication and focal hypermutation, which has been described in cone snails, appear to be common mechanisms to venomous mollusks and spiders. Post-translational modifications, fine structural variations and new molecular scaffolds are other potential mechanisms of toxin diversification, leading to the pharmacologically complex cocktails used for predation and defense.

Keywords

combinatorial libraries molecular scaffold peptides pharmacology spider venom 

Abbreviations

HPLC

High-Performance Liquid Chromatography

MALDI-TOF MS

Matrix-Assisted Laser desorption/ionization Time-Of-Flight Mass Spectrometry

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    King G.F., The wonderful world of spiders: Preface to the special toxicon issue on spider venoms, Toxicon, 43 (2004) 471–476CrossRefGoogle Scholar
  2. 2.
    Escoubas P., Diochot S., Corzo G., Structure and pharmacology of spider venom neurotoxins, Biochimie, 82 (2000) 893–907CrossRefGoogle Scholar
  3. 3.
    Rash L.D., Hodgson W.C., Pharmacology and biochemistry of spider venoms, Toxicon, 40 (2002) 225–254CrossRefGoogle Scholar
  4. 4.
    Olivera B.M., Cruz L.J., Conotoxins, in retrospect, Toxicon, 39 (2001) 7–14CrossRefGoogle Scholar
  5. 5.
    Escoubas, P., Sollod, B.L. and King, G.F., Venom landscapes: Mining the complexity of spider venoms via a combined cDNA and mass spectrometric approach, Toxicon (2006, in press)Google Scholar
  6. 6.
    Pimenta A.M., Rates B., Bloch C. Jr., Gomes P.C., Santoro M.M., de Lima M.E., Richardson M., Cordeiro Mdo N., Electrospray ionization quadrupole time-of-flight and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometric analyses to solve micro-heterogeneity in post-translationally modified peptides from Phoneutria nigriventer (Aranea, Ctenidae) venom, Rapid Commun. Mass Spectrom., 19 (2005) 31–37CrossRefGoogle Scholar
  7. 7.
    Pimenta A.M., Stöcklin R., Favreau P., Bougis P.E., Martin-Eauclaire M.F., Moving pieces in a proteomic puzzle: Mass fingerprinting of toxic fractions from the venom of Tityus serrulatus (Scorpiones, Buthidae), Rapid Commun. Mass Spectrom., 15 (2001) 1562–1572CrossRefGoogle Scholar
  8. 8.
    Lewis R.J., Garcia M.L., Therapeutic potential of venom peptides, Nat. Rev. Drug. Discov., 2 (2003) 790–802CrossRefGoogle Scholar
  9. 9.
    Escoubas P., Rash L., Tarantulas: Eight-legged pharmacists and combinatorial chemists, Toxicon, 43 (2004) 555–574CrossRefGoogle Scholar
  10. 10.
    King G.F., Tedford H.W., Maggio F., Structure and function of insecticidal neurotoxins from Australian funnel-web spiders, J. Toxicol. Toxin Rev., 21 (2002) 359–389CrossRefGoogle Scholar
  11. 11.
    Escoubas P., Célérier M.L., Nakajima T., High-performance liquid chromatography matrix-assisted laser desorption/ionization time-of-flight mass spectrometry peptide fingerprinting of tarantula venoms in the genus Brachypelma: Chemotaxonomic and biochemical applications, Rapid Commun. Mass Spectrom., 11 (1997) 1891–1899CrossRefGoogle Scholar
  12. 12.
    Escoubas P., Whiteley B.J., Kristensen C.P., Célérier M.L., Corzo G., Nakajima T., Multidimensional peptide fingerprinting by high performance liquid chromatography, capillary zone electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for the identification of tarantula venom samples, Rapid Commun. Mass Spectrom., 12 (1998) 1075–1084CrossRefGoogle Scholar
  13. 13.
    Escoubas P., Chamot-Rooke J., Stöcklin R., Whiteley B.J., Corzo G., Genet R., Nakajima T., A comparison of matrix-assisted laser desorption/ionization time-of-flight and liquid chromatography electrospray ionization mass spectrometry methods for the analysis of crude tarantula venoms in the Pterinochilus group, Rapid Commun. Mass Spectrom.,13 (1999) 1861–1868CrossRefGoogle Scholar
  14. 14.
    Escoubas P., Corzo G., Whiteley B.J., Célérier M.L., Nakajima T., Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and high-performance liquid chromatography study of quantitative and qualitative variation in tarantula spider venoms, Rapid Commun. Mass Spectrom., 16 (2002) 403–413CrossRefGoogle Scholar
  15. 15.
    Norton R.S., Pallaghy P.K., The cystine knot structure of ion channel toxins and related polypeptides, Toxicon, 36 (1998) 1573–1583CrossRefGoogle Scholar
  16. 16.
    Sanguinetti M.C., Johnson J.H., Hammerland L.G., Kelbaugh P.R., Volkmann R.A., Saccomano N.A., Mueller A.L., Heteropodatoxins: Peptides isolated from spider venom that block Kv4.2 potassium channels, Mol. Pharmacol., 51 (1997) 491–498Google Scholar
  17. 17.
    Diochot S., Drici M.D., Moinier D., Fink M., Lazdunski M., Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of Ito1 in cardiac electrogenesis, Br. J. Pharmacol., 126 (1999) 251–263CrossRefGoogle Scholar
  18. 18.
    Oswald R.E., Suchyna T.M., McFeeters R., Gottlieb P., Sachs F., Solution structure of peptide toxins that block mechanosensitive ion channels, J. Biol. Chem., 277 (2002) 34443–34450CrossRefGoogle Scholar
  19. 19.
    Middleton R.E., Warren V.A., Kraus R.L., Hwang J.C., Liu C.J., Dai G., Brochu R.M., Kohler M.G., Gao Y.D., Garsky V.M., Bogusky M.J., Mehl J.T., Cohen C.J., Smith M.M., Two tarantula peptides inhibit activation of multiple sodium channels, Biochemistry, 41 (2002) 14734–14747CrossRefGoogle Scholar
  20. 20.
    Wang X.-H., Connor M., Smith R., Maciejewski M.W., Howden M. E.H., Nicholson G.M., Christie M.J., King G.F., Discovery and characterization of a family of insecticidal neurotoxins with a rare vicinal disulfide bond, Nat. Struct. Biol., 7 (2000) 505–513CrossRefGoogle Scholar
  21. 21.
    Shu Q., Huang R., Liang S., Assignment of the disulfide bonds of huwentoxin-II by Edman degradation sequencing and stepwise thiol modification, Eur. J. Biochem., 268 (2001) 2301–2307CrossRefGoogle Scholar
  22. 22.
    Shu Q., Lu S.Y., Gu X.C., Liang S.P., Sequence-specific Assignment of (1)H-NMR resonance and determination of the secondary structure of HWTX-II, Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao, 33 (2001) 65–70Google Scholar
  23. 23.
    Shu Q., Lu S.Y., Gu X.C., Liang S.P., The structure of spider toxin huwentoxin-II with unique disulfide linkage: Evidence for structural evolution, Protein Sci., 11 (2002) 245–252CrossRefGoogle Scholar
  24. 24.
    Diniz C.R., Cordeiro Mdo N., Junor L.R., Kelly P., Fischer S., Reimann F., Oliveira E.B., Richardson M., The purification and amino acid sequence of the lethal neurotoxin Tx1 from the venom of the Brazilian ‚armed’ spider Phoneutria nigriventer, FEBS Lett., 263 (1990) 251–253CrossRefGoogle Scholar
  25. 25.
    Szeto T.H., Wang X.H., Smith R., Connor M., Christie M.J., Nicholson G.M., King G.F., Isolation of a funnel-web spider polypeptide with homology to mamba intestinal toxin 1 and the embryonic head inducer Dickkopf-1, Toxicon, 38 (2000) 429–442CrossRefGoogle Scholar
  26. 26.
    Escoubas P., Célérier M.-L., Romi-Lebrun R., Nakajima T., Two novel peptide toxins from the venom of the tarantula Lasiodora parahybana, Toxicon, 35 (1997) 805CrossRefGoogle Scholar
  27. 27.
    Corzo G., Villegas E., Gomez-Lagunas F., Possani L.D., Belokoneva O.S., Nakajima T., Oxyopinins, large amphipathic peptides isolated from the venom of the wolf spider Oxyopes kitabensis with cytolytic properties and positive insecticidal cooperativity with spider neurotoxins, J. Biol. Chem., 277 (2002) 23627–23637CrossRefGoogle Scholar
  28. 28.
    Belokoneva O.S., Villegas E., Corzo G., Dai L., Nakajima T., The hemolytic activity of six arachnid cationic peptides is affected by the phosphatidylcholine-to-sphingomyelin ratio in lipid bilayers, Biochim. Biophys. Acta, 1617(2003) 22–30CrossRefGoogle Scholar
  29. 29.
    Adams M.E., Bindokas V.P., Hasegawa L., Venema V.J., Omega-agatoxins: Novel calcium channel antagonists of two subtypes from funnel web spider (Agelenopsis aperta) venom , J. Biol. Chem., 265(1990) 861–867Google Scholar
  30. 30.
    Lampe R.A., Defeo P.A., Davison M.D., Young J., Herman J.L., Spreen R.C., Horn M.B., Mangano T.J., Keith R.A., Isolation and pharmacological characterization of omega-grammotoxin SIA, a novel peptide inhibitor of neuronal voltage-sensitive calcium channel responses, Mol Pharmacol., 44(1993) 451–460Google Scholar
  31. 31.
    Piser T.M., Lampe R.A., Keith R.A., Thayer S.A., Omega-grammotoxin SIA blocks multiple, voltage-gated, Ca2+ channel subtypes in cultured rat hippocampal neurons, Mol. Pharmacol., 48(1995) 131–139Google Scholar
  32. 32.
    McDonough S.I., Lampe R.A., Keith R.A., Bean B.P., Voltage-dependent inhibition of – and P-type calcium channels by the peptide toxin omega-grammotoxin-SIA, Mol. Pharmacol., 52(1997)1095–1104Google Scholar
  33. 33.
    Newcomb R., Szoke B., Palma A., Wang G., Chen X., Hopkins W., Cong R., Miller J., Urge L., Tarczy-Hornoch K., Loo J.A., Dooley D.J., Nadasdi L., Tsien R.W., Lemos J., Miljanich G., Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas, Biochemistry, 37(1998) 15353–15362CrossRefGoogle Scholar
  34. 34.
    Bourinet E., Stotz S.C., Spaetgens R.L., Dayanithi G., Lemos J., Nargeot J., Zamponi G.W., Interaction of SNX482 with domains III and IV inhibits activation gating of alpha(1E) (Ca(V)2.3) calcium channels, Biophys. J., 81(2001) 79–88CrossRefGoogle Scholar
  35. 35.
    Tedford H.W., Sollod B.L., Maggio F., King G.F., Australian funnel-web spiders: Master insecticide chemists, Toxicon, 43(2004) 601–618CrossRefGoogle Scholar
  36. 36.
    Swartz K.J., MacKinnon R., An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula, Neuron, 15(1995) 941–949CrossRefGoogle Scholar
  37. 37.
    Swartz K.J., MacKinnon R., Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites, Neuron, 18(1997) 665–673CrossRefGoogle Scholar
  38. 38.
    Swartz K.J., MacKinnon R., Mapping the receptor site for hanatoxin, a gating modifier of voltage- dependent K+ channels, Neuron, 18(1997) 675–682CrossRefGoogle Scholar
  39. 39.
    Zhou Y., Morais-Cabral J.H., Kaufman A., MacKinnon R., Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A° resolution, Nature, 414(2001) 43–48CrossRefGoogle Scholar
  40. 40.
    Escoubas P., Diochot S., Célérier M.L., Nakajima T., Lazdunski M., Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies, Mol Pharmacol., 62(2002) 48–57CrossRefGoogle Scholar
  41. 41.
    Li-Smerin Y., Swartz K.J., Localization and molecular determinants of the Hanatoxin receptors on the voltage-sensing domains of a K(+) channel, J. Gen. Physiol., 115(2000) 673–684CrossRefGoogle Scholar
  42. 42.
    Lou K.L., Huang P.T., Shiau Y.S., Shiau Y.Y., Molecular determinants of the hanatoxin binding in voltage-gated K+- channel drk1, J. Mol. Recognit., 15(2002) 175–179CrossRefGoogle Scholar
  43. 43.
    Ruta V., Jiang Y., Lee A., Chen J., MacKinnon R., Functional analysis of an archaebacterial voltage-dependent K(+) channel , Nature 422(2003) 180–185CrossRefGoogle Scholar
  44. 44.
    Lou K.L., Huang P.T., Shiau Y.S., Liaw Y.C., Shiau Y.Y., Liou H.H., A possible molecular mechanism of hanatoxin binding-modified gating in voltage-gated K+-channels, J. Mol. Recognit., 16(2003) 392–395CrossRefGoogle Scholar
  45. 45.
    Huang P.T., Chen T.Y., Tseng L.J., Lou K.L., Liou H.H., Lin T.B., Spatz H.C., Shiau Y.Y., Structural influence of hanatoxin binding on the carboxyl terminus of S3 segment in voltage-gated K(+)-channel Kv2.1, Receptors Channels, 8(2002) 79–85CrossRefGoogle Scholar
  46. 46.
    Shiau Y.S., Lin T.B., Liou H.H., Huang P.T., Lou K.L., Shiau Y.Y., Molecular simulation reveals structural determinants of the hanatoxin binding in Kv2.1 channels, J. Mol. Model. (online), 8(2002) 253–257CrossRefGoogle Scholar
  47. 47.
    Winterfield J.R., Swartz K.J., A hot spot for the interaction of gating modifier toxins with voltage-dependent ion channels, J. Gen. Physiol., 116 (2000) 637–644CrossRefGoogle Scholar
  48. 48.
    Li-Smerin Y., Swartz K.J., Gating modifier toxins reveal a conserved structural motif in voltage-gated Ca2+ and K+ channels, Proc. Natl. Acad. Sci. USA, 95(1998) 8585–8589CrossRefGoogle Scholar
  49. 49.
    Takahashi H., Kim J.I., Min H.J., Sato K., Swartz K.J., Shimada I., Solution structure of hanatoxin1, a gating modifier of voltage- dependent K(+) channels: Common surface features of gating modifier toxins, J. Mol. Biol., 297 (2000) 771–780CrossRefGoogle Scholar
  50. 50.
    Lee C.W., Kim S., Roh S.H., Endoh H., Kodera Y., Maeda T., Kohno T., Wang J.M., Swartz K.J., Kim J.I., Solution structure and functional characterization of SGTx1, a modifier of Kv2.1 channel gating, Biochemistry, 43(2004) 890–897Google Scholar
  51. 51.
    Chagot B., Escoubas P., Villegas E., Bernard C., Ferrat G., Corzo G., Lazdunski M., Darbon H., Solution structure of Phrixotoxin 1, a specific peptide inhibitor of Kv4 potassium channels from the venom of the theraphosid spider Phrixotrichus auratus, Protein Sci.,13 (2004) 1197–1208CrossRefGoogle Scholar
  52. 52.
    Jiang Y., Ruta V., Chen J., Lee A., MacKinnon R., The principle of gating charge movement in a voltage-dependent K+ channel, Nature, 423 (2003) 42–48CrossRefGoogle Scholar
  53. 53.
    Jung H.J., Lee J.Y., Kim S.H., Eu Y.J., Shin S.Y., Milescu M., Swartz K.J., Kim J.I., Solution structure and lipid membrane partitioning of VSTx1, an inhibitor of the KvAP potassium channel, Biochemistry, 44 (2005) 6015–6023CrossRefGoogle Scholar
  54. 54.
    Lee H.C., Wang J.M., Swartz K.J., Interaction between extracellular Hanatoxin and the resting conformation of the voltage-sensor paddle in Kv channels, Neuron, 40(2003) 527–536CrossRefGoogle Scholar
  55. 55.
    Liang S., An overview of peptide toxins from the venom of the Chinese bird spider Selenocosmia huwena Wang [=Ornithoctonus huwena (Wang)], Toxicon, 43 (2004) 575–585CrossRefGoogle Scholar
  56. 56.
    Bosmans F., Rash L., Zhu S., Diochot S., Lazdunski M., Escoubas P., Tytgat J., Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes, Mol. Pharmacol., (2005) Google Scholar
  57. 57.
    Nicholson G.M., Little M.J., Birinyi-Strachan L.C., Structure and function of δ-atracotoxins: Lethal neurotoxins targeting the voltage-gated sodium channel, Toxicon, 43 (2004) 587–599CrossRefGoogle Scholar
  58. 58.
    Corzo G., Escoubas P., Villegas E., Karbat I., Gordon D., Gurevitz M., Nakajima T., Gilles N., A spider toxin that induces a typical effect of scorpion alpha-toxins but competes with beta-toxins on binding to insect sodium channels, Biochemistry, 44 (2005)1542–1549CrossRefGoogle Scholar
  59. 59.
    Xiao Y., Tang J., Yang Y., Wang M., Hu W., Xie J., Zeng X., Liang S., Jingzhaotoxin-III, a novel spider toxin inhibiting activation of voltage-gated sodium channel in rat cardiac myocytes, J. Biol. Chem., 279 (2004) 26220–26226CrossRefGoogle Scholar
  60. 60.
    Xiao Y., Tang J., Hu W., Xie J., Maertens C., Tytgat J., Liang S., Jingzhaotoxin-I, a novel spider neurotoxin preferentially inhibiting cardiac sodium channel inactivation, J. Biol. Chem., 280 (2005)12069–12076CrossRefGoogle Scholar
  61. 61.
    Li D., Xiao Y., Hu W., Xie J., Bosmans F., Tytgat J., Liang S., Function and solution structure of hainantoxin-I, a novel insect sodium channel inhibitor from the Chinese bird spider Selenocosmia hainana, FEBS Lett., 555 (2003) 616–622CrossRefGoogle Scholar
  62. 62.
    Liu Z., Dai J., Chen Z., Hu W., Xiao Y., Liang S., Isolation and characterization of hainantoxin-IV, a novel antagonist of tetrodotoxin-sensitive sodium channels from the Chinese bird spider Selenocosmia hainana, Cell. Mol. Life Sci., 60 (2003)972–978CrossRefGoogle Scholar
  63. 63.
    Xiao Y., Liang S, Inhibition of neuronal tetrodotoxin-sensitive Na+ channels by two spider toxins: Hainantoxin-III and hainantoxin-IV, Eur. J. Pharmacol., 477 (2003) 1–7CrossRefGoogle Scholar
  64. 64.
    Xiao Y.C., Liang S.P., Purification and characterization of Hainantoxin-V, a tetrodotoxin-sensitive sodium channel inhibitor from the venom of the spider Selenocosmia hainana, Toxicon, 41 (2003) 643–650CrossRefGoogle Scholar
  65. 65.
    Escoubas P., De Weille J.R., Lecoq A., Diochot S., Waldmann R., Champigny G., Moinier D., Ménez A., Lazdunski M., Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels, J. Biol. Chem., 275 (2000) 25116–25121CrossRefGoogle Scholar
  66. 66.
    Chen X., Kalbacher H., Grunder S., The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity, J. Gen. Physiol., 126 (2005) 71–79CrossRefGoogle Scholar
  67. 67.
    Escoubas P., Bernard C., Lambeau G., Lazdunski M., Darbon H., (2003) Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels, Protein Sci., 12 (2003)1332–1343CrossRefGoogle Scholar
  68. 68.
    Salinas M., Rash L.D., Baron A., Lambeau G., Escoubas P., Lazdunski M., (2006) The receptor site of the spider toxin PcTx1 on the proton-gated cation channel, ASIC1a, J. Physiol., 570 (2006) 339–354Google Scholar
  69. 69.
    Vukicevic M., Weder G., Boillat A., Boesch A., Kellenberger S., Trypsin cleaves acid-sensing ion channel 1a in a domain that is critical for channel gating, J. Biol. Chem., 281 (2006) 714–722CrossRefGoogle Scholar
  70. 70.
    Ménez A., Functional architectures of animal toxins: A clue to drug design? Toxicon, 36 (1998) 1557–1572CrossRefGoogle Scholar
  71. 71.
    Duda T.F. Jr., Palumbi S.R., Molecular genetics of ecological diversification: Duplication and rapid evolution of toxin genes of the venomous gastropod Conus, Proc. Natl. Acad. Sci. USA, 96 (1999) 6820–6823CrossRefGoogle Scholar
  72. 72.
    Olivera B.M., Hillyard D.R., Marsh M., Yoshikami D., (1995) Combinatorial peptide libraries in drug design: Lessons from venomous cone snails, Trends Biotechnol., 13 (1995) 422–426CrossRefGoogle Scholar
  73. 73.
    Sollod B.L., Wilson D., Zhaxybayeva O., Gogarten J.P., Drinkwater R., King G., (2005) Were arachnids the first to use combinatorial peptide libraries? Peptides, 26 (2005) 131–139CrossRefGoogle Scholar
  74. 74.
    Diao J., Lin Y., Tang J., Liang S., cDNA sequence analysis of seven peptide toxins from the spider Selenocosmia huwena, Toxicon, 42 (2003) 715–723CrossRefGoogle Scholar
  75. 75.
    Kozlov S., Malyavka A., McCutchen B., Lu A., Schepers E., Herrmann R., Grishin E., A novel strategy for the identification of toxinlike structures in spider venom, Proteins, 59 (2005) 131–140CrossRefGoogle Scholar
  76. 76.
    Buczek, O., Bulaj, G. and Olivera, B.M., Conotoxins and the posttranslational modification of secreted gene products, Cell. Mol. Life Sci., 62 (2005) 3067–3079Google Scholar
  77. 77.
    Kuwada M., Teramoto T., Kumagaye K.Y., Nakajima K., Watanabe T., Kawai T., Kawakami Y., Niidome T., Sawada K., Nishizawa Y. et al., Omega-agatoxin-TK containing D-serine at position 46, but not synthetic omega-[L-Ser46]agatoxin-TK, exerts blockade of P-type calcium channels in cerebellar Purkinje neurons, Mol. Pharmacol., 46 (1994) 587–593Google Scholar
  78. 78.
    Branton W.D., Rudnick M.S., Zhou Y., Eccleston E.D., Fields G.B., Bowers L.D., Fatty acylated toxin structure, Nature, 365 (1993) 496–497CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) – CNRS UMR 6097ValbonneFrance

Personalised recommendations