Biological Activities of Snake Venom Metalloproteinases on Platelets, Neutrophils, Endothelial Cells, and Extracellular Matrices

  • Chun-Chieh Hsu
  • Tur-Fu HuangEmail author


Snake venom metalloproteinases (SVMPs) may be classified into P-I~P-IV SVMP. P-I and P-III groups are abundant in viper venoms, and preserve proteolytic activity. These zinc-dependent SVMPs have profound effects on cellular receptors, plasma proteins and extracellular matrices, and thus affecting haemostasis. In this review, we focus on their interaction with platelet glycoprotein (GP) Ib, GP VI, integrin α2β1, neutrophil PSGL-1, endothelial adherens junction, plasma vWF, fibrinogen and other extracellular matrix, e.g. collagen, in causing antiplatelet, antiinflammation, and endothelial apoptosis. In addition, the in vivo antithrombotic and hemorrhagic activities of these SVMPs are also explored. Through these structure-activity relationship studies using SVMPs as tools for elucidating the ligand-receptor interaction, we may devise useful antidotes for thrombosis, inflammation and human victims of snake envenoming.


Snake Venom Protease Domain Coagulation Factor VIII Venom Component Metalloproteinase Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Araki, S., Masuda, S., Maeda, H., Ying, M.J., Hayashi, H., 2002. Involvement of specific integrins in apoptosis induced by vascular apoptosis-inducing protein 1. Toxicon 40, 535–542.CrossRefPubMedGoogle Scholar
  2. Blanchot-Jossic, F., Jarry, A., Masson, D., Bach-Ngohou, K., Paineau, J., Denis, M.G., Laboisse, C.L., Mosnier, J.F., 2005. Up-regulated expression of ADAM17 in human colon carcinoma: co-expression with EGFR in neoplastic and endothelial cells. J. Pathol. 207, 156–163.CrossRefPubMedGoogle Scholar
  3. Chang, M.C., Lin, H.K., Peng, H.C., Huang, T.F., 1998. Antithrombotic effect of crotalin, a platelet membrane glycoprotein Ib antagonist from venom of Crotalus atrox. Blood 91, 1582–1589.PubMedGoogle Scholar
  4. De Luca, M., Dunlop, L.C., Andrews, R.K., Flannery, J.V., Jr., Ettling, R., Cumming, D.A., Veldman, G.M., Berndt, M.C., 1995. A novel cobra venom metalloproteinase, mocarhagin, cleaves a 10-amino acid peptide from the mature N terminus of P-selectin glycoprotein ligand receptor, PSGL-1, and abolishes P-selectin binding. J. Biol. Chem. 270, 26734–26737.CrossRefPubMedGoogle Scholar
  5. Fox, J.W., Serrano, S.M., 2008. Insights into and speculations about snake venom metalloproteinase (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity. FEBS J. 275, 3016–3030.CrossRefPubMedGoogle Scholar
  6. Hsu, C.C., Wu, W.B., Chang, Y.H., Kuo, H.L., Huang, T.F., 2007. Antithrombotic effect of a protein-type I class snake venom metalloproteinase, kistomin, is mediated by affecting glycoprotein Ib-von Willebrand factor interaction. Mol. Pharmacol. 72, 984–992.CrossRefPubMedGoogle Scholar
  7. Hsu, C.C., Wu, W.B., Huang, T.F., 2008. A snake venom metalloproteinase, kistomin, cleaves platelet glycoprotein VI and impairs platelet functions. J. Thromb. Haemost. 6, 1578–1585.PubMedGoogle Scholar
  8. Huang, T.F., Chang, M.C., Teng, C.M., 1993. Antiplatelet protease, kistomin, selectively cleaves human platelet glycoprotein Ib. Biochim. Biophys. Acta 1158, 293–299.CrossRefPubMedGoogle Scholar
  9. Huang, T.F., 1998. What have snakes taught us about integrins? Cell. Mol. Life Sci. 54, 527–540.CrossRefGoogle Scholar
  10. Kamiguti, A.S., Desmond, H.P., Theakston, R.D., Hay, C.R., Zuzel, M., 1994. Ineffectiveness of the inhibition of the main haemorrhagic metalloproteinase from Bothrops jararaca venom by its only plasma inhibitor, alpha 2-macroglobulin. Biochim. Biophys. Acta 1200, 307–314.CrossRefPubMedGoogle Scholar
  11. Kamiguti, A.S., Hay, C.R., Zuzel, M., 1996. Inhibition of collagen-induced platelet aggregation as the result of cleavage of α2β1-integrin by the snake venom metalloproteinase jararhagin. Biochem. J. 320, 635–641.PubMedGoogle Scholar
  12. Kamiguti, A.S., Markland, F.S., Zhou, Q., Laing, G.D., Theakston, R.D., Zuzel, M., 1997. Proteolytic cleavage of the beta1 subunit of platelet alpha2beta1 integrin by the metalloproteinase jararhagin compromises collagen-stimulated phosphorylation of pp72. J. Biol. Chem. 272, 32599–325605.CrossRefPubMedGoogle Scholar
  13. Kamiguti, A.S., Gallagher, P., Marcinkiewicz, C., Theakston, R.D., Zuzel, M., Fox, J.W., 2003. Identification of sites in the cysteine-rich domain of the class P-III snake venom metalloproteinases responsible for inhibition of platelet function. FEBS Lett. 549, 129–134.CrossRefPubMedGoogle Scholar
  14. Kawano, J., Anai, K., Sugiki, M., Yoshida, E., Maruyama, M., 2002. Vascular endothelial cell injury induced by Bothrops jararaca venom; non-significance of hemorrhagic metalloproteinase. Toxicon 40, 1553–1562.CrossRefPubMedGoogle Scholar
  15. Laing, G.D., Moura-da-Silva, A.M., 2005. Jararhagin and its multiple effects on hemostasis. Toxicon 45, 987–996.CrossRefPubMedGoogle Scholar
  16. Liu, C.Z., Huang, T.F., 1997. Crovidisin, a collagen-binding protein isolated from snake venom of Crotalus viridis, prevents platelet-collagen interaction. Arch. Biochem. Biophys. 337, 291–299.CrossRefPubMedGoogle Scholar
  17. Masuda, S., Hayashi, H., Araki, S., 1998. Two vascular apoptosis-inducing proteins from snake venom are members of the metalloprotease/disintegrin family. Eur. J. Biochem. 253, 36–41.CrossRefPubMedGoogle Scholar
  18. Masuda, S., Ohta, T., Kaji, K., Fox, J.W., Hayashi, H., Araki, S., 2000. cDNA cloning and characterization of vascular apoptosis-inducing protein 1. Biochem. Biophys. Res. Commun. 278, 197–204.CrossRefPubMedGoogle Scholar
  19. Murphy, G., 2008. The ADAMs: signalling scissors in the tumour microenvironment. Nat. Rev. Cancer. 8, 929–941.CrossRefPubMedGoogle Scholar
  20. Nurden, P., Nurden, A.T., 2008. Congenital disorders associated with platelet dysfunctions. Thromb. Haemost. 99, 253–263.PubMedGoogle Scholar
  21. Oldenburg, J., El-Maarri, O., 2006. New insight into the molecular basis of hemophilia A. Int. J. Hematol. 83, 96–102.CrossRefPubMedGoogle Scholar
  22. Rocks, N., Paulissen, G., El Hour, M., Quesada, F., Crahay, C., Gueders, M., Foidart, J.M., Noel, A., Cataldo, D., 2008. Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie 90, 369–379.CrossRefPubMedGoogle Scholar
  23. Saidi, N., Samel, M., Siigur, J., Jensen, P.E., 1999. Lebetase, an alpha(beta)-fibrin(ogen)olytic metalloproteinase of Vipera lebetina snake venom, is inhibited by human alpha-macroglobulins. Biochim. Biophys. Acta 1434, 94–102.CrossRefPubMedGoogle Scholar
  24. Sottrup-Jensen, L., 1989. Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation. J. Biol. Chem. 264, 11539–11542.PubMedGoogle Scholar
  25. Souza, C.T., Moura, M.B., Magalhaes, A., Heneine, L.G., Olortegui, C.C., Diniz, C.R., Sanchez, E.F., 2001. Inhibition of mutalysin II, a metalloproteinase from bushmaster snake venom by human alpha2-macroglobulin and rabbit immunoglobulin. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 130, 155–168.CrossRefPubMedGoogle Scholar
  26. Tseng, Y.L., Lee, C.J., Hsu, C.C., Huang, T.F. 2004a. Triflamp, a snake venom metalloproteinase, reduces neutrophil-platelet adhesion through proteolysis of PSGL-1 but not glycoprotein Ib alpha. Thromb. Haemost. 91, 1177–1185.PubMedGoogle Scholar
  27. Tseng, Y.L., Lee, C.J., Huang, T.F., 2004b. Effects of a snake venom metalloproteinase, triflamp, on platelet aggregation, platelet-neutrophil and neutrophil-neutrophil interactions: involvement of platelet GPIbalpha and neutrophil PSGL-1. Thromb. Haemost. 91, 315–324.PubMedGoogle Scholar
  28. Tseng, Y.L., Wu, W.B., Hsu, C.C., Peng, H.C., Huang, T.F., 2004c. Inhibitory effects of human alpha2-macroglobulin and mouse serum on the PSGL-1 and glycoprotein Ib proteolysis by a snake venom metalloproteinase, triflamp. Toxicon 43, 769–777.CrossRefPubMedGoogle Scholar
  29. van Goor, H., Melenhorst, W.B., Turner, A.J., Holgate, S.T., 2009. Adamalysins in biology and disease. J. Pathol. 219, 277–286.CrossRefPubMedGoogle Scholar
  30. Wang, W.J., Shih, C.H., Huang, T.F., 2005. Primary structure and antiplatelet mechanism of a snake venom metalloproteinase, acurhagin, from Agkistrodon acutus venom. Biochimie 87, 1065–1077.CrossRefPubMedGoogle Scholar
  31. Wang, W.J., 2007. Purification and functional characterization of AAV1, a novel P-III metalloproteinase, from Formosan Agkistrodon acutus venom. Biochimie 89, 105–115.CrossRefPubMedGoogle Scholar
  32. Ward, C.M., Andrews, R.K., Smith, A.I., Berndt, M.C., 1996. Mocarhagin, a novel cobra venom metalloproteinase, cleaves the platelet von Willebrand factor receptor glycoprotein Ibalpha. Identification of the sulfated tyrosine/anionic sequence Tyr-276-Glu-282 of glycoprotein Ibalpha as a binding site for von Willebrand factor and alpha-thrombin. Biochemistry 35, 4929–4938.CrossRefPubMedGoogle Scholar
  33. Wu, W.B., Peng, H.C., Huang, T.F., 2001a. Crotalin, a vWF and GP Ib cleaving metalloproteinase from venom of Crotalus atrox. Thromb. Haemost. 86, 1501–1511.PubMedGoogle Scholar
  34. Wu, W.B., Chang, S.C., Liau, M.Y., Huang, T.F., 2001b. Purification, molecular cloning and mechanism of action of graminelysin I, a snake-venom-derived metalloproteinase that induces apoptosis of human endothelial cells. Biochem. J. 357, 719–728.CrossRefPubMedGoogle Scholar
  35. Wu, W.B., Huang, T.F., 2003. Activation of MMP-2, cleavage of matrix proteins, and adherens junctions during a snake venom metalloproteinase-induced endothelial cell apoptosis. Exp. Cell. Res. 288, 143–157.CrossRefPubMedGoogle Scholar
  36. Zhou, Q., Dangelmaier, C., Smith, J.B., 1996. The hemorrhagin catrocollastatin inhibits collagen-induced platelet aggregation by binding to collagen via its disintegrin-like domain. Biochem. Biophys. Res. Commun. 219, 720–726.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Institute of Pharmacology, College of Medicine, National Taiwan UniversityTaipeiTaiwan
  2. 2.Graduate Institute of Pharmacology, College of Medicine, National Taiwan UniversityTaipeiTaiwan

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