Brief History and Molecular Determinants of Snake Venom Disintegrin Evolution

  • Juan J. CalveteEmail author


Disintegrins represent a family of polypeptides released in the venoms of Viperidae and Crotalidae snakes (vipers and rattlesnakes) by the proteolytic processing of PII Zn2+-metalloproteinases or synthesized from short-coding mRNAs. Disintegrins selectively block the function of β1 and β3 integrin receptors. This review summarizes our current view and hypotheses on the emergence and on the structural and functional diversification of disintegrins.


Disulfide Bond Snake Venom Integrin Receptor Venom Gland Venom Protein 
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.



Research on disintegrins has been continuously financed by grants from the Ministerio de Ciencia y Tecnología and Ministerio de Educación y Ciencia, Madrid, Spain.


  1. Bazaa, A., Juárez, P., Marrakchi, N., Lasfer, Z.B., El Ayeb, M., Harrison, R.A., Calvete, J.J., Sanz, L., 2007. Loss of introns along the evolutionary diversification pathway of snake venom disintegrins evidenced by sequence analysis of genomic DNA from Macrovipera lebetina transmediterranea and Echis ocellatus. J. Mol. Evol. 64, 261–271.PubMedCrossRefGoogle Scholar
  2. Bilgrami, S., Tomar, S. Yadav, S., Kaur, P., Kumar, J., Jabeen, T., Sharma, S., Singh, T.P., 2004. Crystal structure of schistatin, a disintegrin homodimer from saw-scaled viper (Echis carinatus) at 2.5 Å resolution. J. Mol. Biol. 341, 829–837.PubMedCrossRefGoogle Scholar
  3. Bilgrami, S., Yadav, S. Sharma, S., Perbandt, M., Betzel, C., Singh, T.P., 2005. Crystal structure of the disintegrin heterodimer from saw-scaled viper (Echis carinatus) at 1.9 Å resolution. Biochemistry 44, 11058–11066.PubMedCrossRefGoogle Scholar
  4. Calvete, J.J., Schrader, M., Raida, M., McLane, M.A., Romero, A., Niewiarowski, S., 1997. The disulphide bond pattern of bitistatin, a disintegrin isolated from the venom of the viper Bitis arietans. FEBS Lett. 416, 197–202.PubMedCrossRefGoogle Scholar
  5. Calvete, J.J., Jürgens, M., Marcinkiewicz, C., Romero, A., Schrader, M., Niewiarowski, S., 2000. Disulfide bond pattern and molecular modelling of the dimeric disintegrin EMF-10, a potent and selective integrin α5β1 antagonist from Eristocophis macmahoni venom. Biochem. J. 345, 573–581.PubMedCrossRefGoogle Scholar
  6. Calvete, J.J., Fox, J.W., Agelan, A., Niewiarowski, S., Marcinkiewicz, C., 2002. The presence of the WGD motif in CC8 heterodimeric disintegrin increases its inhibitory effect on αIIbβ3, αvβ3, and α5β1 integrins. Biochemistry 41, 2014–2021.PubMedCrossRefGoogle Scholar
  7. Calvete, J.J., Moreno-Murciano, M.P., Theakston, R.D.G., Kisiel, D.G., Marcinkiewicz, C., 2003. Snake venom disintegrins: novel dimeric disintegrins and structural diversification by disulfide bond engineering. Biochem. J. 372, 725–734.PubMedCrossRefGoogle Scholar
  8. Calvete, J.J., 2005. Structure-function correlations of snake venom disintegrins. Curr. Pharm. Des. 11, 829–835.PubMedCrossRefGoogle Scholar
  9. Calvete, J.J., Marcinkiewicz, C., Monleón, D., Esteve, V., Celda, B., Juárez, P., Sanz, L., 2005. Snake venom disintegrins: evolution of structure and function. Toxicon 45, 1063–1074.PubMedCrossRefGoogle Scholar
  10. Calvete, J.J., Marcinkiewicz, C., Sanz, L., 2007. KTS- and RTS-disintegrins: anti-angiogenic viper venom peptides specifically targeting the α1β1 integrin. Curr. Pharm. Des. 13, 2853–2859.PubMedCrossRefGoogle Scholar
  11. Calvete, J.J., Juárez, P., Sanz, L., 2009. Snake venomics and disintegrins. Portrait and evolution of a family of snake venom integrin antagonists, in: Mackessy, S.P. (Ed.), Handbook of Venoms and Toxins of Reptiles. CRC Press, Taylor & Francis, Boca Raton, 337–357.CrossRefGoogle Scholar
  12. Calvete, J.J., 2010. Snake venomics, antivenomics, and venom phenotyping: the ménage à trois of proteomic tools aimed at understanding the biodiversity of venoms, in: Kini, R.M., Clemetson, K.J., Markland, F.S., McLane, M.A., Morita, T. (Eds.), Toxins and Hemostasis: From Bench to Bedside. Springer, Dordrecht, The Netherlands.Google Scholar
  13. Calvete, J.J., Sanz, L., Cid, P., De La Torre, P., Flores-Díaz, M., Dos Santos, M.C., Borges, A., Bremo, A., Angulo, Y., Lomonte, B., Alape-Girón, A., Gutiérrez, J.M., 2010. Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along Crotalus dispersal in South America. J. Proteome Res. 9(1), 528–544.Google Scholar
  14. Castoe, T.A., Parkinson, C.L., 2006. Bayesian mixed models and the phylogeny of pitvipers (Viperidae: Serpentes). Mol. Phylogenet. Evol. 39, 91–110.PubMedCrossRefGoogle Scholar
  15. Castoe, T.A., Daza, J.M., Smith, E.N., Sasa, M., Kuch, U., Campbell, J.A., Chippindale, P.T., Parkinson, C.L., 2009. Comparative phylogeography of pitvipers suggests a consensus of ancient Middle American highland biogeography. J. Biogeogr. 36, 88–103.CrossRefGoogle Scholar
  16. De Lima, M.E., Pimenta, A.M.C., Martin-Euclaire, M.F., Zingali, R.B., 2009. Animal Toxins: State of the Art. Perspectives in Health and Biotechnology. Editora UFMG, Belo Horizonte.Google Scholar
  17. Fox, J.W., Serrano, S.M., 2005. Snake toxins and hemostasis. Toxicon 45, 951–1181.CrossRefGoogle Scholar
  18. Fox, J.W., Serrano, S.M.T., 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.PubMedCrossRefGoogle Scholar
  19. Fox, J.W., Serrano, S.M., 2009. Timeline of key events in snake venom metalloproteinase research. J. Proteomics 72, 200–209.PubMedCrossRefGoogle Scholar
  20. Fry, B.G., Vidal, N., Norman, J.A., Vonk, F.J., Scheib, H., Ramjan, S.F., Kuruppu, S., Fung, K., Hedges, S.B., Richardson, M.K., Hodgson, W.C., Ignjatovic, V., Summerhayes, R., Kochva, E., 2006. Early evolution of the venom system in lizards and snakes. Nature 439, 584–588.PubMedCrossRefGoogle Scholar
  21. Fry, B.G., Vidal, N., van der Weerd, L., Kochva, E., Renjifo, C., 2009. Evolution and diversification of the Toxicofera reptile venom system. J. Proteomics 72, 127–136.PubMedCrossRefGoogle Scholar
  22. Glassey, B, Civetta, A., 2004. Positive selection at reproductive ADAM genes with potential intercellular binding activity. Mol. Biol. Evol. 21:851–859.PubMedCrossRefGoogle Scholar
  23. Hughes, A.L., 1994. The evolution of functionally novel proteins after gene duplication. Proc. Roy. Soc. London Scr. B. 256, 119–124.CrossRefGoogle Scholar
  24. Hughes, A.L., 2000. Adaptive Evolution of Genes and Genomes. Oxford University Press, Oxford.Google Scholar
  25. Jia, L-G., Shimokawa, K-I., Bjarnason, J.B., Fox, J.W., 1996. Snake venom metalloproteinases: structure, function and relationship to the ADAMs family of proteins. Toxicon 34, 1269–1276.PubMedCrossRefGoogle Scholar
  26. Juárez, P., Wagstaff, S.C., Oliver, J., Sanz, L., Harrison, R.A., Calvete, J.J., 2006a. Molecular cloning of disintegrin-like transcript BA-5A from Bitis arietans venom gland cDNA library: a putative intermediate in the evolution of the long chain disintegrin bitistatin. J. Mol. Evol. 63, 142–152.PubMedCrossRefGoogle Scholar
  27. Juárez, P., Wagstaff, S.C., Sanz, L., Harrison, R.A., Calvete, J.J., 2006b. Molecular cloning of Echis ocellatus disintegrins reveals non-venom-secreted proteins and a pathway for the evolution of ocellatusin. J. Mol. Evol. 63, 183–193.PubMedCrossRefGoogle Scholar
  28. Juárez, P., Comas, I., González-Candelas, F., Calvete, J.J., 2008. Evolution of snake venom disintegrins by positive Darwinian selection. Mol. Biol. Evol. 25, 2391–2407.PubMedCrossRefGoogle Scholar
  29. Kini, R.M., Evans, H.J., 1992. Structural domains in venom proteins: evidence that metalloproteinases and nonenzymatic platelet aggregation inhibitors (disintegrins) from snake venoms are derived by proteolysis from a common precursor. Toxicon 30, 265–293.PubMedCrossRefGoogle Scholar
  30. Lenk, P., Kalyabina, S., Wink, M., Joger, U., 2001. Evolutionary relationships among the true vipers (Reptilia: Viperidae) inferred from mitochondrial dna sequences. Mol. Phylogenet. Evol. 19, 94–104.PubMedCrossRefGoogle Scholar
  31. Mackessy, S.P., 2009. Handbook of Venoms and Toxins of Reptiles. CRC Press, Taylor & Francis, Boca Ratón.CrossRefGoogle Scholar
  32. Mazzi, M.V., Magro, A.J., Amui, S.F., Oliveira, C.Z., Ticli, F.K., Stábeli, R.G., Fuly, A.L., Rosa, J.C., Braz, A.S.K., Fontes, M.R.M., Sampai, S.V., Soares, A.M., 2007. Molecular characterization and phylogenetic analysis of BjussuMP-I: a RGD-P-III class hemorrhagic metalloprotease from Bothrops jararacussu snake venom. J. Mol. Graph. Model. 26, 69–85.PubMedCrossRefGoogle Scholar
  33. McLane, M.A., Marcinkiewicz, C., Vijay-Kumar, S., Wierbzbicka-Patynowski, I., Niewiarowski, S., 1998. Viper venom disintegrins and related molecules. Proc. Soc. Exp. Biol. Med. 219, 109–119.PubMedGoogle Scholar
  34. Marcinkiewicz, C., Calvete, J.J., Marcinkiewicz, M.M., Raida, M., Vijay-Kumar, S., Huang, Z., Lobb, R.R., Niewiarowski, S., 1999. EC3, a novel heterodimeric disintegrin from Echis carinatus venom, inhibits α4 and α5 integrins in an RGD-independent manner. J. Biol. Chem. 274, 12468–12473.PubMedCrossRefGoogle Scholar
  35. Marcinkiewicz, C., Taooka, Y., Yokosaki, Y., Calvete, J.J., Marcinkiewicz, M.M., Lobb, R.R., Niewiarowski, S., Sheppard, D., 2000. Inhibitory effects of MLDG-containing heterodimeric disintegrins reveal distinct structural requirements for interaction of the integrin α9β1 with VCAM-1, tenascin-C, and osteopontin. J. Biol. Chem. 275, 31930–31937.PubMedCrossRefGoogle Scholar
  36. Marcinkiewicz, C., 2005. Functional characteristics of snake venom disintegrins: potential therapeutic implications. Curr. Pharm. Des. 11, 815–827.PubMedCrossRefGoogle Scholar
  37. Monleón, D., Moreno-Murciano, M.P., Kovacs, H., Marcinkiewicz, C., Calvete, J.J., Celda, B., 2003. Concerted motions of the integrin-binding loop and the C-terminal tail of the non-RGD disintegrin obtustatin. J. Biol. Chem. 278, 45570–45576.PubMedCrossRefGoogle Scholar
  38. Monleón, D., Esteve, V., Kovacs, H., Calvete, J.J., Celda, B., 2005. Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR. Biochem. J. 387, 57–66.PubMedCrossRefGoogle Scholar
  39. Moreno-Murciano, M.P., Monleón, D., Marcinkiewicz, C., Calvete, J.J., Celda, B., 2003. NMR solution structure of the non-RGD disintegrin obtustatin. J. Mol. Biol. 329, 135–145.CrossRefGoogle Scholar
  40. Moura da Silva, A.M., Theakston, R.D.G., Crampton, J.M., 1996. Evolution of disintegrin cysteine-rich and mammalian matrix-degrading metalloproteinases: gene duplication and divergence of a common ancestor rather than convergent evolution. J. Mol. Evol. 43, 263–269.CrossRefGoogle Scholar
  41. Nei, M., Gu, X., Sitnikova, T., 1997. Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proc. Natl. Acad. Sci. U.S.A. 94, 7799–7806.PubMedCrossRefGoogle Scholar
  42. Niewiarowski, S., McLane, M.A., Kloczewiak, M., Stewart, G.J., 1994. Disintegrins and other naturally occurring antagonists of platelet fibrinogen receptors. Semin. Hematol. 31, 289–300.PubMedGoogle Scholar
  43. Nikai, T., Taniguchi, K., Komori,Y., Masuda, K., Fox, J.W., Sugihara, S., 2000. Primary structure and functional characterization of bilitoxin-1, a novel dimeric P-II snake venom metalloproteinase from Agkistrodon bilineatus venom. Arch. Biochem. Biophys. 378, 6–15.PubMedCrossRefGoogle Scholar
  44. Ogawa, T., Chijiwa, T., Oda-Ueda, N., Ohno, M., 2005. Molecular diversity and accelerated evolution of C-type lectin-like proteins from snake venom. Toxicon 45, 1–14.PubMedCrossRefGoogle Scholar
  45. Okuda, D., Koike, H., Morita, T., 2002. A new gene structure of the disintegrin family: a subunit of dimeric disintegrin has a short coding region. Biochemistry 41, 14248–14254.PubMedCrossRefGoogle Scholar
  46. Sanz, L., Bazaa, A., Marrakchi, N., Pérez, A., Chenik, M., Bel Lasfer, Z., El Ayeb, M., Calvete, J.J., 2006. Molecular cloning of disintegrins from Cerastes vipera and Macrovipera lebetina transmediterranea venom gland cDNA libraries. Insight into the evolution of the snake venom’s integrin inhibition system. Biochem. J. 395, 385–392.PubMedCrossRefGoogle Scholar
  47. Takeda, S., Igarashi, T., Mori, H., Araki, S., 2006. Crystal structures of VAP1 reveal ADAMs’ MDC domain architecture and its unique C-shaped scaffold. EMBO J. 25, 2388–2396.PubMedCrossRefGoogle Scholar
  48. Takeda, S., 2009. Three-dimensional domain architecture of the ADAM family proteinases. Semin. Cell. Dev. Biol., 20, 146–152.PubMedCrossRefGoogle Scholar
  49. Vidal, N., Hedges, S.B., 2002. Higher-level relationships of snakes inferred from four nuclear and mitochondrial genes. C. R. Biol. 325, 977–985.PubMedCrossRefGoogle Scholar
  50. Wu, W.B., Chang, S.C., Liau, M.Y., Huang, T.F., 2001. 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.PubMedCrossRefGoogle Scholar
  51. Wüster, W., Peppin, L., Pook, C.E., Walker, D.E., 2008. A nesting of vipers: phylogeny and historical biogeography of the Viperidae (Squamata: Serpentes). Mol. Phylogenet. Evol. 49, 445–459.PubMedCrossRefGoogle Scholar
  52. Xiong, J-P., Stehle, T., Zhang, R., Joachimiak, A., Frech, M., Goodman, S.L., Arnaout, M.A., 2002. The crystal structure of the extracellular segment of integrin αvβ3 in complex with an Arg-Gly-Asp ligand. Science 296, 151–155.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Laboratorio de Proteinómica EstructuralInstituto de Biomedicina de Valencia, CSICValenciaSpain

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