Many snake venom proteins have been isolated that affect platelet plug formation by interacting either with platelet integrins, membrane glycoprotein Ib (GPIb), or plasma von Willebrand factor (VWF). Among them, disintegrins purified from various snake venoms are strong inhibitors of platelet aggregation. Botrocetin and bitiscetin derived from Bothrops jararaca and Bitis arietans venom, respectively, induce VWF-dependent platelet agglutination in vitro. Several GPIb-binding proteins have also been isolated from snake venoms. In this review, we focus on the structure and function of those snake venom proteins that influence platelet plug formation. These proteins are potentially useful as reagents for the sub-diagnosis of platelet disorder or von Willebrand disease, as well as for clinical and basic research of thrombosis and hemostasis.
References
[1]
Sadler, J.E. von Willebrand factor: Two sides of a coin. J. Thromb. Haemost.？2005, 3, 1702–1709. 16102036
[2]
Ruggeri, Z.M. The role of von Willebrand factor in thrombus formation. Thromb. Res.？2007, 120 (Suppl 1), S5–S9, doi:10.1016/j.thromres.2007.03.011. 17493665
[3]
Ouyang, C.; Teng, C.M.; Huang, T.F. Characterization of snake venom components acting on blood coagulation and platelet function. Toxicon？1992, 30, 945–966. 1440652
[4]
Matsui, T.; Fujimura, Y.; Titani, K. Snake venom proteases affecting hemostasis and thrombosis. Biochim. Biophys. Acta？2000, 1477, 146–156. 10708855
[5]
Matsui, T.; Hamako, J. Structure and function of snake venom toxins interacting with human von Willebrand factor. Toxicon？2005, 45, 1075–1087. 15922776
Marsh, N.; Williams, V. Practical applications of snake venom toxins in haemostasis. Toxicon？2005, 45, 1171–1181. 15922782
[9]
Clemetson, K.J.; Clemetson, J.M. Platelet GPIb complex as a target for anti-thrombotic drug development. Thromb. Haemost.？2008, 99, 473–479. 18327394
[10]
Huang, T.F.; Holt, J.C.; Lukasiewicz, H.; Niewiarowski, S. Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. J. Biol. Chem.？1987, 262, 16157–16163. 3680247
[11]
Huang, T.F.; Holt, J.C.; Kirby, E.P.; Niewiarowski, S. Trigramin: Primary structure and its inhibition of von Willebrand factor binding to glycoprotein IIb/IIIa complex on human platelets. Biochemistry？1989, 28, 661–666. 2653425
[12]
McLane, M.A.; Paquette-Straub, C. Scientific and standardization committee communications: Classification and nomenclature of disintegrins isolated from snake venoms. J. Thromb. Haemost.？2007, 5, 1971. 17596129
Moiseeva, N.; Bau, R.; Swenson, S.D.; Markland, F.S., Jr.; Choe, J.Y.; Liu, Z.J.; Allaire, M. Structure of acostatin, a dimeric disintegrin from Southern copperhead (Agkistrodon contortrix contortrix), a.7 A resolution. Acta Crystallogr. D. Biol. Crystallogr.？2008, 64, 466–470. 18391413
[15]
Adler, M.; Lazarus, R.A.; Dennis, M.S.; Wagner, G. Solution structure of kistrin, a potent platelet aggregation inhibitor and GP IIb-IIIa antagonis. Science？1991, 253, 445–448. 1862345
[16]
Monleon, D.; Esteve, V.; Kovacs, H.; Calvete, J.J.; Celda, B. Conformation and concerted dynamics of the integrin-binding site and the C-terminal region of echistatin revealed by homonuclear NMR. Biochem. J.？2005, 387, 57–66. 15535803
[17]
Fujii, Y.; Okuda, D.; Fujimoto, Z.; Horii, K.; Morita, T.; Mizuno, H. Crystal structure of trimestatin, a disintegrin containing a cell adhesion recognition motif RG. J. Mol. Biol.？2003, 332, 1115–1122. 14499613
[18]
Shin, J.; Hong, S.Y.; Chung, K.; Kang, I.; Jang, Y.; Kim, D.S.; Lee, W. Solution structure of a novel disintegrin, salmosin, from Agkistrondon halys ven. Biochemistry？2003, 42, 14408–14415. 14661951
[19]
Bilgrami, S.; Tomar, S.; Yadav, S.; Kaur, P.; Kumar, J.; Jabeen, T.; Sharma, S.; Singh, T.P. Crystal structure of schistatin, a disintegrin homodimer from saw-scaled viper (Echis carinatus) at .5 A resolution. J. Mol. Biol.？2004, 341, 829–837, doi:10.1016/j.jmb.2004.06.048. 15317139
[20]
Bilgrami, S.; Yadav, S.; Kaur, P.; Sharma, S.; Perbandt, M.; Betzel, C.; Singh, T.P. Crystal structure of the disintegrin heterodimer from saw-scaled viper (Echis carinatus) at 1.9 A resolution. Biochemistry？2005, 44, 11058–11066. 16101289
[21]
Sayle, R.A.; Milner-White, E.J. RASMOL: Biomolecular graphics for all. Trends. Biochem. Sci.？1995, 20, 374. 7482707
[22]
Kim, J.; Hong, S.Y.; Park, H.S.; Kim, D.S.; Lee, W. Structure and function of RGD peptides derived from disintegrin proteins. Mol. Cells？2005, 19, 205–211. 15879703
[23]
Scarborough, R.M.; Rose, J.W.; Hsu, M.A.; Phillips, D.R.; Fried, V.A.; Campbell, A.M.; Nannizzi, L.; Charo, I.F. Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. J. Biol. Chem.？1991, 266, 9359–9362. 2033037
[24]
Scarborough, R.M.; Naughton, M.A.; Teng, W.; Rose, J.W.; Phillips, D.R.; Nannizzi, L.; Arfsten, A.; Campbell, A.M.; Charo, I.F. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa. J. Biol. Chem？1993, 268, 1066–1073. 8419315
[25]
Scarborough, R.M. Development of eptifibatide. Am. Heart. J.？1999, 138, 1093–1104. 10577440
[26]
Phillips, D.R.; Scarborough, R.M. Clinical pharmacology of eptifibatide. Am. J. Cardiol.？, 80, 11–20. 9291241
[27]
Plosker, G.L.; Ibbotson, T. Eptifibatide: A pharmacoeconomic review of its use in percutaneous coronary intervention and acute coronary syndromes. Pharmacoeconomics？2003, 21, 885–912. 12908844
[28]
Zeymer, U.; Wienbergen, H. A review of clinical trials with eptifibatide in cardiology. Cardiovasc. Drug Rev.？2007, 25, 301–315. 18078431
[29]
Sheffield, W.P.; Gataiance, S.; Eltringham-Smith, L.J. Combined administration of barbourin-albumin and hirudin-albumin fusion proteins limits fibrin(ogen) deposition on the rabbit balloon-injured aorta. Thromb. Res.？2007, 119, 195–207. 16478628
[30]
Lu, X.; Lu, D.; Scully, M.F.; Kakkar, V.V. Snake venom metalloproteinase containing a disintegrin-like domain, its structure-activity relationships at interacting with integrin. Curr. Med. Chem. Cardiovasc. Hematol. Agents？2005, 3, 249–260. 15974889
[31]
McLane, M.A.; Marcinkiewicz, C.; Vijay-Kumar, S.; Wierzbicka-Patynowski, I.; Niewiarowski, S. Viper venom disintegrins and related molecules. Proc. Soc. Exp. Biol. Med.？1998, 219, 109–119. 9790167
[32]
Myles, D.G.; Kimmel, L.H.; Blobel, C.P.; White, J.M.; Primakoff, P. Identification of a binding site in the disintegrin domain of fertilin required for sperm-egg fusion. Proc. Natl. Acad. Sci. USA？1994, 91, 4195–4198.
[33]
Yagami-Hiromasa, T.; Sato, T.; Kurisaki, T.; Kamijo, K.; Nabeshima, Y.; Fujisawa-Sehara, A. A metalloprotease-disintegrin participating in myoblast fusion. Nature？1995, 377, 652–656. 7566181
[34]
Blobel, C.P. Metalloprotease-disintegrins: Links to cell adhesion and cleavage of TNF alpha and Notch. Cell？1997, 90, 589–592. 9288739
[35]
Ito, M.; Hamako, J.; Sakurai, Y.; Matsumoto, M.; Fujimura, Y.; Suzuki, M.; Hashimoto, K.; Titani, K.; Matsui, T. Complete amino acid sequence of kaouthiagin, a novel cobra venom metalloproteinase with two disintegrin-like sequence. Biochemistry？2001, 40, 4503–4511. 11284707
[36]
Hamako, J.; Matsui, T.; Nishida, S.; Nomura, S.; Fujimura, Y.; Ito, M.; Ozeki, Y.; Titani, K. Purification and characterization of kaouthiagin, a von Willebrand factor-binding and -cleaving metalloproteinase from Naha kaouthia cobra veno. Thromb. Haemost.？1998, 80, 499–505. 9759634
[37]
Brinkhous, K.M.; Fricke, W.A.; Read, M.S. Determinants of von Willebrand factor activity elicited by ristocetin and botrocetin: Studies on a human von Willebrand factor-binding antibody. Semin. Thromb. Hemost.？1985, 11, 337–341. 2416059
[38]
Scott, J.P.; Montgomery, R.R.; Retzinger, G.S. Dimeric ristocetin flocculates proteins, binds to platelets, and mediates von Willebrand factor-dependent agglutination of platele. J. Biol. Chem.？1991, 266, 8149–8155. 2022635
[39]
Read, M.S.; Shermer, R.W.; Brinkhous, K.M. Venom coagglutinin: An activator of platelet aggregation dependent on von Willebrand factor. Proc. Natl. Acad. Sci. USA？1978, 75, 4514–4518.
[40]
Read, M.S.; Smith, S.V.; Lamb, M.A.; Brinkhous, K.M. Role of botrocetin in platelet agglutination: Formation of an activated complex of botrocetin and von Willebrand factor. Blood？1989, 74, 1031–1035. 2473809
[41]
Usami, Y.; Fujimura, Y.; Suzuki, M.; Ozeki, Y.; Nishio, K.; Fukui, H.; Titani, K. Primary structure of two-chain botrocetin, a von Willebrand factor modulator purified from the venom of Bothrops jararac. Proc. Natl. Acad. Sci. USA？1993, 90, 928–932.
[42]
Matsui, T.; Hamako, J.; Suzuki, M.; Hayashi, N.; Ito, M.; Makita, K.; Fujimura, Y.; Ozeki, Y.; Titani, K. Complete amino acid sequence of bitiscetin, a novel von Willebrand factor modulator protein, purified from snake venom of Bitis arieta. Res. Commun. Biochem. Cell Mol. Biol.？1997, 1, 271–284.
[43]
Kawasaki, T.; Fujimura, Y.; Usami, Y.; Suzuki, M.; Miura, S.; Sakurai, Y.; Makita, K.; Taniuchi, Y.; Hirano, K.; Titani, K. Complete amino acid sequence and identification of the platelet glycoprotein Ib-binding site of jararaca GPIb-BP, a snake venom protein isolated from Bothrops jararac. J. Biol. Chem.？1996, 271, 10635–10639. 8631868
[44]
Fukuda, K.; Doggett, T.; Laurenzi, I.J.; Liddington, R.C.; Diacovo, T.G. The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation. Nat. Struct. Mol. Biol.？2005, 12, 152–159. 15665869
[45]
Sen, U.; Vasudevan, S.; Subbarao, G.; McClintock, R.A.; Celikel, R.; Ruggeri, Z.M.; Varughese, K.I. Crystal structure of the von Willebrand factor modulator botrocetin. Biochemistry？2001, 40, 345–352. 11148028
[46]
Hirotsu, S.; Mizuno, H.; Fukuda, K.; Qi, M.C.; Matsui, T.; Hamako, J.; Morita, T.; Titani, K. Crystal structure of bitiscetin, a von Willebrand factor-dependent platelet aggregation induce. Biochemistry？2001, 40, 13592–13597. 11695907
[47]
Matsushita, T.; Meyer, D.; Sadler, J.E. Localization of von willebrand factor-binding sites for platelet glycoprotein Ib and botrocetin by charged-to-alanine scanning mutagenesis. J. Biol. Chem.？2000, 275, 11044–11049. 10753907
[48]
Maita, N.; Nishio, K.; Nishimoto, E.; Matsui, T.; Shikamoto, Y.; Morita, T.; Sadler, J.E.; Mizuno, H. Crystal structure of von Willebrand factor A1 domain complexed with snake venom, bitiscetin: Insight into glycoprotein Ibalpha binding mechanism induced by snake venom protein. J. Biol. Chem.？2003, 278, 37777–37781. 12851390
[49]
Matsui, T.; Hamako, J.; Matsushita, T.; Nakayama, T.; Fujimura, Y.; Titani, K. Binding site on human von Willebrand factor of bitiscetin, a snake venom-derived platelet aggregation induce. Biochemistry？2002, 41, 7939–7946. 12069583
[50]
Obert, B.; Romijn, R.A.; Houllier, A.; Huizinga, E.G.; Girma, J.P. Characterization of bitiscetin-2, a second form of bitiscetin from the venom of Bitis arietans : Comparison of its binding site with the collagen-binding site on the von Willebrand factor A3-domai. J. Thromb. Haemost.？2006, 4, 1596–1601. 16839359
[51]
Mizuno, H.; Fujimoto, Z.; Koizumi, M.; Kano, H.; Atoda, H.; Morita, T. Structure of coagulation factors IX/X-binding protein, a heterodimer of C-type lectin domain. Nat. Struct. Biol.？1997, 4, 438–441. 9187649
[52]
Atoda, H.; Ishikawa, M.; Mizuno, H.; Morita, T. Coagulation factor X-binding protein from Deinagkistrodon acutus venom is a Gla domain-binding protein. Biochemistry？1998, 37, 17361–17370. 9860851
[53]
Fukuda, K.; Mizuno, H.; Atoda, H.; Morita, T. Crystallization and preliminary x-ray studies of flavocetin-A, a platelet glycoprotein Ib-binding protein from the habu snake veno. Acta Crystallogr. D. Biol. Crystallogr.？1999, 55, 1911–1913. 10531492
[54]
Murakami, M.T.; Zela, S.P.; Gava, L.M.; Michelan-Duarte, S.; Cintra, A.C.; Arni, R.K. Crystal structure of the platelet activator convulxin, a disulfide-linked alpha4beta4 cyclic tetramer from the venom of Crotalus durissus terrificu. Biochem. Biophys. Res. Commun.？2003, 310, 478–482. 14521935
[55]
Moreland, J.L.; Gramada, A.; Buzko, O.V.; Zhang, Q.; Bourne, P.E. The Molecular Biology Toolkit (MBT): A modular platform for developing molecular visualization applications. BMC Bioinf.？2005, 6, 21.
[56]
Miura, S.; Li, C.Q.; Cao, Z.; Wang, H.; Wardell, M.R.; Sadler, J.E. Interaction of von Willebrand factor domain A1 with platelet glycoprotein Ibalpha-(1-289). Slow intrinsic binding kinetics mediate rapid platelet adhesion. J. Biol. Chem.？2000, 275, 7539–7546. 10713059
[57]
Fukuda, K.; Doggett, T.A.; Bankston, L.A.; Cruz, M.A.; Diacovo, T.G.; Liddington, R.C. Structural basis of von Willebrand factor activation by the snake toxin botrocetin. Structure？2002, 10, 943–950. 12121649
[58]
Marchese, P.; Murata, M.; Mazzucato, M.; Pradella, P.; De Marco, L.; Ware, J.; Ruggeri, Z.M. Identification of three tyrosine residues of glycoprotein Ib alpha with distinct roles in von Willebrand factor and alpha-thrombin binding. J. Biol. Chem.？1995, 270, 9571–9578. 7721887
[59]
Dong, J.; Ye, P.; Schade, A.J.; Gao, S.; Romo, G.M.; Turner, N.T.; McIntire, L.V.; Lopez, J.A. Tyrosine sulfation of glycoprotein I(b)alpha. Role of electrostatic interactions in von Willebrand factor binding. J. Biol. Chem.？2001, 276, 16690–16694. 11279169
[60]
Peng, M.; Lu, W.; Kirby, E.P. Alboaggregin-B: A new platelet agonist that binds to platelet membrane glycoprotein Ib. Biochemistry？1991, 30, 11529–11536. 1747371
[61]
Peng, M.; Lu, W.; Kirby, E.P. Characterization of three alboaggregins purified from Trimeresurus albolabris venom. Thromb. Haemost.？1992, 67, 702–707. 1509413
[62]
Sakurai, Y.; Fujimura, Y.; Kokubo, T.; Imamura, K.; Kawasaki, T.; Handa, M.; Suzuki, M.; Matsui, T.; Titani, K.; Yoshioka, A. The cDNA cloning and molecular characterization of a snake venom platelet glycoprotein Ib-binding protein, mamushigin, from Agkistrodon halys blomhoffii ven. Thromb. Haemost.？1998, 79, 1199–1207. 9657448
[63]
Du, X.Y.; Navdaev, A.; Clemetson, J.M.; Magnenat, E.; Wells, T.N.; Clemetson, K.J. Bilinexin, a snake C-type lectin from Agkistrodon bilineatus venom agglutinates platelets via GPIb and alpha2beta. Thromb. Haemost.？2001, 86, 1277–1283. 11816718
[64]
Wang, W.J.; Huang, T.F. A novel tetrameric venom protein, agglucetin from Agkistrodon acutus, acts as a glycoprotein Ib agoni. Thromb. Haemost.？2001, 86, 1077–1086. 11686327
[65]
Xu, G.; Ulrichts, H.; Vauterin, S.; De Meyer, S.F.; Deckmyn, H.; Teng, M.; Niu, L. How does agkicetin-C bind on platelet glycoprotein Ibalpha and achieve its platelet effects? Toxicon？2005, 45, 561–570. 15777951
[66]
Lu, Q.; Navdaev, A.; Clemetson, J.M.; Clemetson, K.J. GPIb is involved in platelet aggregation induced by mucetin, a snake C-type lectin protein from Chinese habu (Trimeresurus mucrosquamatus) veno. Thromb. Haemost.？2004, 91, 1168–1176. 15175804
[67]
Huang, K.F.; Ko, T.P.; Hung, C.C.; Chu, J.; Wang, A.H.; Chiou, S.H. Crystal structure of a platelet-agglutinating factor isolated from the venom of Taiwan habu (Trimeresurus mucrosquamatus). Biochem. J.？2004, 378, 399–407. 14613481
[68]
Wang, W.J.; Ling, Q.D.; Liau, M.Y.; Huang, T.F. A tetrameric glycoprotein Ib-binding protein, agglucetin, from Formosan pit viper: Structure and interaction with human platele. Thromb. Haemost.？2003, 90, 465–475. 12958616
[69]
Lu, Q.; Clemetson, J.M.; Clemetson, K.J. Translocation of GPIb and Fc receptor gamma-chain to cytoskeleton in mucetin-activated platelets. J. Thromb. Haemost.？2005, 3, 2065–2076. 16102113
[70]
Peng, M.; Lu, W.; Beviglia, L.; Niewiarowski, S.; Kirby, E.P. Echicetin: A snake venom protein that inhibits binding of von Willebrand factor and alboaggregins to platelet glycoprotein Ib. Blood？1993, 81, 2321–2328. 8481512
[71]
Taniuchi, Y.; Kawasaki, T.; Fujimura, Y.; Suzuki, M.; Titani, K.; Sakai, Y.; Kaku, S.; Hisamichi, N.; Satoh, N.; Takenaka, T. Flavocetin-A and -B, two high molecular mass glycoprotein Ib binding proteins with high affinity purified from Trimeresurus flavoviridis venom, inhibit platelet aggregation at high shear stres. Biochim. Biophys. Acta？1995, 1244, 331–338.
[72]
Kawasaki, T.; Taniuchi, Y.; Hisamichi, N.; Fujimura, Y.; Suzuki, M.; Titani, K.; Sakai, Y.; Kaku, S.; Satoh, N.; Takenaka, T. Tokaracetin, a new platelet antagonist that binds to platelet glycoprotein ib and inhibits von Willebrand factor-dependent shear-induced platelet aggregation. Biochem. J.？1995, 308 (Pt 3), 947–953. 8948455
[73]
Fujimura, Y.; Ikeda, Y.; Miura, S.; Yoshida, E.; Shima, H.; Nishida, S.; Suzuki, M.; Titani, K.; Taniuchi, Y.; Kawasaki, T. Isolation and characterization of jararaca GPIb-BP, a snake venom antagonist specific to platelet glycoprotein I. Thromb. Haemost.？1995, 74, 743–750. 8585016
[74]
Zhong, S.R.; Jin, Y.; Wu, J.B.; Chen, R.Q.; Jia, Y.H.; Wang, W.Y.; Xiong, Y.L.; Zhang, Y. Characterization and molecular cloning of dabocetin, a potent antiplatelet C-type lectin-like protein from Daboia russellii siamensis veno. Toxicon？2006, 47, 104–112. 16330060
[75]
Fukuda, K.; Mizuno, H.; Atoda, H.; Morita, T. Crystal structure of flavocetin-A, a platelet glycoprotein Ib-binding protein, reveals a novel cyclic tetramer of C-type lectin-like heterodime. Biochemistry？2000, 39, 1915–1923. 10684640
[76]
Jasti, J.; Paramasivam, M.; Srinivasan, A.; Singh, T.P. Crystal structure of echicetin from Echis carinatus (Indian saw-scaled viper) at 2.4A resolution. J. Mol. Biol.？2004, 335, 167–176, doi:10.1016/j.jmb.2003.10.048. 14659748
[77]
Xu, G.; Huang, Q.; Teng, M.; Liu, P.; Dong, Y.; Niu, L. Crystallization and preliminary X-ray crystallographic analysis of agkicetin-C from Deinagkistrodon acutus venom. Acta Crystallogr. Sect. F. Struct. Biol. Cryst. Commun.？2005, 61, 75–78. 16508096
[78]
Taniuchi, Y.; Kawasaki, T.; Fujimura, Y. The high molecular mass, glycoprotein Ib-binding protein flavocetin-A induces only small platelet aggregates in vitr. Thromb. Res.？2000, 97, 69–75. 10688335
[79]
Peng, M.; Holt, J.C.; Niewiarowski, S. Isolation, characterization and amino acid sequence of echicetin beta subunit, a specific inhibitor of von Willebrand factor and thrombin interaction with glycoprotein. Biochem. Biophys. Res. Commun.？1994, 205, 68–72. 7999097
[80]
Williams, W. Endangered species. CITES puts off plan to hasten shipments. Science？2000, 288, 592, doi:10.1126/science.288.5466.592. 10798989
[81]
Zeymer, U. The role of eptifibatide in patients undergoing percutaneous coronary intervention. Expert Opin. Pharmacother.？2007, 8, 1147–1154. 17516878
[82]
Hoppe-Seyler, F.; Crnkovic-Mertens, I.; Tomai, E.; Butz, K. Peptide aptamers: Specific inhibitors of protein function. Curr. Mol. Med.？2004, 4, 529–538. 15267224
[83]
Liu, J.; Joglekar, M.; Ware, J.; Fitzgerald, M.E.; Lowell, C.A.; Berndt, M.C.; Gartner, T.K. Evaluation of the physiological significance of botrocetin/von Willebrand factor in vitro signaling. J. Thromb. Haemost.？2008, 6, 1915–1922. 18752568
[84]
Liu, J.; Fitzgerald, M.E.; Berndt, M.C.; Jackson, C.W.; Gartner, T.K. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood？2006, 108, 2596–2603. 16788103
