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The M-superfamily of conotoxins: a review

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Abstract

The focus of this review is the M-superfamily of Conus venom peptides. Disulfide rich peptides belonging to the M-superfamily have three loop regions and the cysteine arrangement: CC–C–C–CC, where the dashes represent loops one, two, and three, respectively. Characterization of M-superfamily peptides has demonstrated that diversity in cystine connectivity occurs between different branches of peptides even though the cysteine pattern remains consistent. This superfamily is subdivided into five branches, M-1 through M-5, based on the number of residues in the third loop region, between the fourth and fifth cysteine residues. M-superfamily peptides appear to be ubiquitous in Conus venom. They are largely unexplained in indigenous biological function, and they represent an active area of research within the scientific community.

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References

  1. Franco A, Pisarewicz K, Moller C, Mora D, Fields GB, Mari F (2006) Hyperhydroxylation: a new strategy for neuronal targeting by venomous marine molluscs. Prog Mol Subcell Biol 43:83–103

    CAS  PubMed  Google Scholar 

  2. Myers RA, Cruz LJ, Rivier JE, Olivera BM (1993) Conus peptides as chemical probes for receptors and ion channels. Chem Rev 93(5):1923–1936

    Article  CAS  Google Scholar 

  3. Kohn AJ, Nishi M, Pernet B (1999) Snail spears and scimitars: a character analysis of Conus radular teeth. J Mollus Stud 65:461–481

    Article  Google Scholar 

  4. McDougal OM, Turner MW, Ormond AJ, Poulter CD (2008) Three-dimensional structure of conotoxin tx3a: an m-1 branch peptide of the M-superfamily. Biochemistry 47:2826–2832

    Article  CAS  PubMed  Google Scholar 

  5. Olivera BM, Cruz LJ (2001) Conotoxins, in retrospect. Toxicon 39:7–14

    Article  CAS  PubMed  Google Scholar 

  6. Kohn AJ (1956) Piscivorous gastropods of the genus Conus. Proc Natl Acad Sci USA 42:168–171

    Article  CAS  PubMed  Google Scholar 

  7. Spence I, Gillessen D, Gregson RP, Quinn RJ (1997) Characterization of the neurotoxic constituents of Conus geographus (L) venom. Life Sci 21:1759–1770

    Article  Google Scholar 

  8. Clark C, Olivera BM, Cruz LJ (1981) A toxin from Conus geographus venom which acts on the vertebrate central nervous system. Toxicon 19:691–699

    Article  CAS  PubMed  Google Scholar 

  9. Jiang H, Wang CZ, Xu CQ, Fan CX, Dai XD, Chen JS, Chi CW (2006) A novel M-superfamily conotoxin with a unique motif from Conus vexillum. Peptides 27:682–689

    Article  CAS  PubMed  Google Scholar 

  10. Olivera BM (1997) Conus venom peptides, receptor and ion channel targets and drug design: 50 million years of neuropharmacology. Mol Biol Cell 8:2101–2109

    CAS  PubMed  Google Scholar 

  11. Norton RS, Olivera BM (2006) Conotoxins down under. Toxicon 48:780–798

    Article  CAS  PubMed  Google Scholar 

  12. Holford M, Zhang MM, Gowd KH, Azam L, Green BR, Watkins M, Ownby JP, Yoshikami D, Bulaj G, Olivera BM (2009) Pruning nature: biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon 53:90–98

    Article  CAS  PubMed  Google Scholar 

  13. McDougal OM (1998) Conus peptides investigated by NMR spectroscopic methods. Doctoral dissertation, University of Utah

  14. Yao S, Zhang MM, Yoshikami D, Azam L, Olivera BM, Bulaj G, Norton RS (2008) Structure, dynamics, and selectivity of the sodium channel blocker (mu)-conotoxin SIIIA. Biochemistry 47:10940–10949

    Article  CAS  PubMed  Google Scholar 

  15. Kass Q, Westermann JC, Halai R, Wang CK, Craik DJ (2008) ConoServer, a database for conopeptide sequences and structures. Bioinformatics 24(3):445–446

    Article  CAS  Google Scholar 

  16. Mehdiratta R, Saberwal G (2007) Bio-business in brief: the case of conotoxins. Curr Sci 92(1):39–45

    CAS  Google Scholar 

  17. Watkins M, Olivera BM, Hillyard DR, McIntosh JM, Jones RM (2007) Alpha-conotoxin peptides. United States Patent 7,279,549. 2007

    Google Scholar 

  18. Alonso D, Khalil Z, Stakunanthan N, Livett BG (2003) Drugs from the sea: conotoxins as drug leads for neuropathic pain and other neurological conditions. Mini Rev Med Chem 3:785–787

    Article  CAS  PubMed  Google Scholar 

  19. Bowersox SS, Luther R (1998) Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus. Toxicon 36(11):1651–1658

    Article  CAS  PubMed  Google Scholar 

  20. Atanassoff PG, Hartmannsgruber MW, Thrasher J, Wermeling D, Longton W, Gaeta R, Singh T, Mayo M, McGuire D, Luther RR (2000) Ziconotide a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med 25:274–278

    CAS  PubMed  Google Scholar 

  21. Penn RD, Paice JA (2000) Adverse effects associated with the intrathecal administration of ziconotide. Pain 85(1–2):291–296

    Article  CAS  PubMed  Google Scholar 

  22. Levin T, Petrides G, Weiner J, Saravay S, Multz AS, Bailine S (2002) Intractable delirium associated with ziconotide successfully treated with electroconvulsive therapy. Psychosomatics 43:63–66

    Article  PubMed  Google Scholar 

  23. Skov MJ, Beck JC, de Kater AW, Shopp GM (2007) Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class. Int J Toxicol 26(5):411–421

    Article  CAS  PubMed  Google Scholar 

  24. Corpuz GP, Jacobsen RB, Jimenez EC, Watkins M, Walker C, Colledge C, Garrett JE, McDougal O, Li W, Gray WR, Hillyard DR, Rivier J, McIntosh JM, Cruz LJ, Olivera BM (2005) Definition of the M-conotoxin superfamily: characterization of novel peptides from molluscivorous Conus venoms. Biochemistry 44:8176–8186

    Article  CAS  PubMed  Google Scholar 

  25. Han YH, Wang Q, Jiang H, Liu L, Xiao C, Yuan DD, Shao XX, Dai QY, Chemng JS, Chi CW (2006) Characterization of novel M-superfamily conotoxins with new disulfide linkage. FEBS J 273:4972–4982

    Article  CAS  PubMed  Google Scholar 

  26. Du WH, Han YH, Huang FJ, Li J, Chi CW, Fang WH (2007) Solution structure of an M-1 conotoxin with a novel disulfide linkage. FEBS J 274:2596–2602

    Article  CAS  PubMed  Google Scholar 

  27. McDougal O, Poulter CD (2004) Three-dimensional structure of the Mini-M conotoxin mr3a. Biochemistry 43:425–429

    Article  CAS  PubMed  Google Scholar 

  28. Wang Q, Jiang H, Han YH, Yuan DD, Chi CW (2008) Two different groups of signal sequence in M-superfamily conotoxins. Toxicon 51:813–822

    Article  CAS  PubMed  Google Scholar 

  29. Ferber M, Sporning A, Jeserich G, DeLaCruz R, Watkins M, Olivera BM, Terlau H (2003) A novel Conus peptide ligand for K + channels. J Biol Chem 278(4):2177–2183

    Article  CAS  PubMed  Google Scholar 

  30. Al-Sabi A, Lennartz D, Ferber M, Gulyas J, Rivier JEF, Olivera BM, Carlomagno T, Terlau H (2004) kappaM-conotoxin RIIIK, structural and functional novelty in a K+ channel antagonist. Biochemistry 43(27):8625–8636

    Article  CAS  PubMed  Google Scholar 

  31. Verdier L, Al-Sabi A, Rivier JEF, Olivera BM, Terlau H, Carlomagno T (2005) Identification of a novel pharmacophore for peptide toxins interacting with K + channels. J Biol Chem 280(22):21246–21255

    Article  CAS  PubMed  Google Scholar 

  32. Khoo KK, Feng ZP, Smith BJ, Zhang MM, Yoshikami D, Olivera BM, Bulaj G, Norton RS (2009) Structure of the analgesic (mu)-conotoxin KIIA and effects on structure and function of disulfide deletion. Biochemistry 48:1210–1219

    Article  CAS  PubMed  Google Scholar 

  33. Sine SM, Engel AG (2006) Recent advances in Cys-loop receptor structure and function. Nature 440:448–455

    Article  CAS  PubMed  Google Scholar 

  34. Lester HA, Dibas MI, Dahan DS, Leite JF, Dougherty DA (2004) Cys-loop receptors: new twists and turns. Trends Neurosci 27(6):229–336

    Article  CAS  Google Scholar 

  35. Cruz LJ, Gray WR, Olivera BM, Zeikus RD, Kerr L, Yoshikami D, Moczydlowski E (1985) Conus geagraphus Toxins that discriminate between neuronal and muscle sodium channels. J Biol Chem 260(16):9280–9288

    CAS  PubMed  Google Scholar 

  36. Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol (Lond) 117:500–544

    CAS  Google Scholar 

  37. Catterall WA (1984) The molecular basis of neuronal excitability. Science 233:653–661

    Article  Google Scholar 

  38. Ferber M, Al-Sabi A, Stocker M, Olivera BM, Terlau H (2004) Identification of a mammalian target of κM-conotoxin RIIIK. Toxicon 43:915–921

    Article  CAS  PubMed  Google Scholar 

  39. Shon K-J, Stocker M, Terlau H, Stuhmer W, Jacobsen R, Walker C, Grilley M, Watkins M, Hillyard DR, Gray WR, Olivera BM (1998) kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K + channel. J Biol Chem 273(1):33–38

    Article  CAS  PubMed  Google Scholar 

  40. Jacobsen RB, Koch ED, Lange-Malecki B, Stocker M, Verhey J, Van Wagoner RM, Vyazovkina A, Olivera BM, Terlau H (2000) Single amino acid substitutions in kappa-conotoxin PVIIA disrupt interaction with the shaker K + channel. J Biol Chem 275(32):24639–24644

    Article  CAS  PubMed  Google Scholar 

  41. Shon KJ, Grilley RJ, Cartier GE, Hopkins C, Gray WR, Watkins M, Hillyard DR, Rivier J, Torrres J, Yoshikami D, Olivera BM (1997) A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom. Biochemistry 36(31):9581–9587

    Article  CAS  PubMed  Google Scholar 

  42. Lluisma AO, Lopez-Vera E, Bulaj G, Watkins M, Olivera BM (2008) Characterization of a novel psi-conotoxin from Conus parius. Toxicon 51:174–180

    Article  CAS  PubMed  Google Scholar 

  43. Van Wagoner RM, Jacobsen RB, Olivera BM, Ireland CM (2003) Characterization and three-dimensional structure determination of psi-conotoxin PIIIF, a novel noncompetitive antagonist of nicotinic acetylcholine receptors. Biochemistry 42(21):6353–6362

    Article  PubMed  CAS  Google Scholar 

  44. Mitchell SS, Shon KJ, Foster MP, Davis DR, Olivera BM, Ireland CM (1998) Three-dimensional solution structure of conotoxin psi-PIIIE, and acetylcholine gated ion channel antagonist. Biochemistry 37(5):1215–1220

    Article  CAS  PubMed  Google Scholar 

  45. Van Wagoner RM, Ireland CM (2003) An improved solution structure for psi-conotoxin PIIIE. Biochemistry 43(21):6347–6352

    Article  CAS  Google Scholar 

  46. Wang C-Z, Zhang H, Jiung H, Lu W, Zhao Z-Q, Chi C-W (2006) A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels. Toxicon 47:122–132

    Article  CAS  PubMed  Google Scholar 

  47. Lewis RJ, Schroeder CI, Ekberg J, Nielson KJ, Loughnan M, Thomas L, Adams DA, Drinkwater R, Adams DJ, Alewood PF (2007) Isolation and structure-activity of mu-conotoxin TIIIA, a potent inhibitor of tetrodotoxin-sensitive voltage-gated sodium channels. Mol Pharmacol 71:676–685

    Article  CAS  PubMed  Google Scholar 

  48. Catterall WA, Goldin AL, Waxman SG (2005) International union of pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57:397–409

    Article  CAS  PubMed  Google Scholar 

  49. Shon KJ, Olivera BM, Watkins M, Jacobsen RB, Gray WR, Floresca CZ, Cruz LJ, Hillyard DR, Brink A, Terlau H, Yoshikami D (1998) mu-Conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes. J Neurosci 18(12):4473–4481

    CAS  PubMed  Google Scholar 

  50. Safo P, Rosenbaum T, Shcherbatko A, Choi DY, Han E, Toledo-Aral JJ, Olivera BM, Brehm P, Mandel G (2000) Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA. J Neurosci 20(1):76–80

    CAS  PubMed  Google Scholar 

  51. Nielsen KJ, Watson M, Adams DJ, Hammarstrom AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ (2002) Solution structure of mu-conotoxin PIIA, a preferential inhibitor of persistent TTX-sensitive sodium channels. J Biol Chem 277:27247–27255

    Article  CAS  PubMed  Google Scholar 

  52. Nakamura M, Niwa Y, Ishida Y, Kohno T, Sato K, Oba Y, Nakumura H (2001) Modification of Arg-13 of μ-conotoxin GIIIA with piperidinyl-Arg analogs and their relation to the inhibition of sodium channels. FEBS Lett 503:107–110

    Article  CAS  PubMed  Google Scholar 

  53. Bulaj G, West PJ, Garrett JE, Watkins M, Zhan M-M, Norton RS, Smith BJ, Yoshikami D, Olivera BM (2005) Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels. Biochemistry 44(19):7259–7265

    Article  CAS  PubMed  Google Scholar 

  54. Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Kallen RG, Mandel G, Meiseler MH, Netter YB (2000) Nomenclature of voltage-gated sodium channels. Neuron 28:365–368

    Article  CAS  PubMed  Google Scholar 

  55. Wada A, Wanke E, Gullo F, Schiavon E (2008) Voltage-dependent Nav1.7 sodium channels: multiple roles in adrenal chromaffin cells and peripheral nervous system. Acta Physiol 192:221–231

    Article  CAS  Google Scholar 

  56. Clare JJ, Tate SN, Nobbs M, Romanos MA (2000) Voltage-gated sodium channels as therapeutic targets. Drug Discov Today 5:506–520

    Article  CAS  PubMed  Google Scholar 

  57. Schroeder CI, Ekberg J, Nielsen KJ, Adams D, Loughnan ML, Thomas L, Adams DJ, Alewood PF, Lewis RJ (2008) Neuronally mu-conotoxins from Conus striatus utilize an alpha-helical motif to target mammalian sodium channels. J Biol Chem 283:21621–21628

    Article  CAS  PubMed  Google Scholar 

  58. Kalso E (2005) Sodium channel blockers in neuropathic pain. Curr Pharm Des 11:3005–3011

    Article  CAS  PubMed  Google Scholar 

  59. Wood JN, Boorman JP, Okuse K, Baker MD (2004) Voltage-gated sodium channels and pain pathways. J Neurobiol 61:55–71

    Article  CAS  PubMed  Google Scholar 

  60. Sato K, Ishida Y, Wakamatsu K, Kato R, Honda H, Ohizumi Y, Nakamura H, Ohya M, Lancelin JM, Kohda D (1991) Active site of mu-conotoxin GIIIA, a peptide blocker of muscle sodium channels. J Biol Chem 266:16989–16991

    CAS  PubMed  Google Scholar 

  61. Hill JM, Alewood PF, Craik DJ (1996) Three-dimensional solution structure of μ-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels. Biochemistry 35:8824–8835

    Article  CAS  PubMed  Google Scholar 

  62. Walewska A, Skalicky JJ, Davis DR, Zhang M-M, Lopez-Vera E, Watkins M, Han TS, Yoshikami D, Olivera BM, Bulaj G (2008) NMR-based mapping of disulfide bridges in cysteine-rich peptides: application to the mu-conotoxin SxIIIA. J Am Chem Soc 130(43):14280–14286

    Article  CAS  PubMed  Google Scholar 

  63. Zhang MM, Fiedler B, Green BR, Catlin P, Watkins M, Garrett JE, Smith BJ, Yoshikami D, Olivera BM, Bulaj G (2006) Structural and functional diversities among mu-conotoxins targeting TTX-resistant sodium channels. Biochemistry 45:3723–3732

    Article  CAS  PubMed  Google Scholar 

  64. West PJ, Bulaj G, Garrett JE, Olivera BM, Yoshikami D (2002) µ-Conotoxin SmIIIA, a potent inhibitor of tetrodotoxin-resistant sodium channels in amphibian sympathetic and sensory neurons. Biochemistry 41(51):15388–15393

    Article  CAS  PubMed  Google Scholar 

  65. Catteral WA (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26:13–25

    Article  Google Scholar 

  66. Keizer DW, West PJ, Lee EF, Yoshikami D, Olivera BM, Bulaj G, Norton RS (2003) Structural basis for tetrodotoxin-resistant sodium channel binding by µ-conotoxin SmIIIA. J Biol Chem 278(47):46805–46813

    Article  CAS  PubMed  Google Scholar 

  67. Moczydlowski E, Olivera BM, Gray WR, Strichartz GR (1986) Discrimination of muscle and neuronal Na-channel subtypes by binding competition between saxitoxin and p-conotoxins. Proc Natl Acad Sci USA 83:5321–5325

    Article  CAS  PubMed  Google Scholar 

  68. Oliveira JS, Redaelli E, Zaharenko AJ, Cassulini RR, Konno K, Pimenta DC, Freitas JC, Clare JJ, Wanke E (2004) Binding specificity of sea anemone toxins to Nav 1.1-1.6 sodium channels: unexpected contributions from differences in the IV/S3–S4 outer loop. J Biol Chem 279:33323–33335

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Drs. Greg Bulaj and Kenneth A. Cornell for their contributions to this manuscript. Additional thanks are owed to Seth Eidemiller, Steven D. Jacob, Matthew Turner, Luke Woodbury, and Aubrey Johnston for their editorial input. This publication was made possible by NIH Grant #P20 RR016454 from the INBRE Program of the National Center for Research Resources, Mountain States Tumor Medical Research Institute, and Research Corporation Cottrell College Scholars Program.

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  1. Department of Chemistry and Biochemistry, Boise State University, 1910 University Drive, Boise, ID, 83725-1520, USA

    Reed B. Jacob & Owen M. McDougal

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Correspondence to Owen M. McDougal.

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Jacob, R.B., McDougal, O.M. The M-superfamily of conotoxins: a review. Cell. Mol. Life Sci. 67, 17–27 (2010). https://doi.org/10.1007/s00018-009-0125-0

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