Binding of von Willebrand Factor to Collagen Type III: Role of Specific Amino Acids in the Collagen Binding Domain of vWF and Effects of Neighboring Domains

 

 Buy Article Permissions and Reprints

Summary

Binding of von Willebrand Factor (vWF) to sites of vascular injury is the first step of hemostasis. Collagen types I and III are important binding sites for vWF. We have previously determined the threedimensional structure of the collagen binding A3 domain of vWF (Huizinga et al., Structure 1997; 5: 1147). We hypothesized that the top face of this domain might be the collagen-binding site. Based on this hypothesis, we made seven vWF mutants (D934A/S936A, V1040A/ V1042A, D1046A, D1066A, D1069A, D1069R, and R1074A). Collagen binding of these mutants was investigated in ELISA and with Surface Plasmon Resonance (BIAcore). In addition, we studied collagen binding of mutants lacking the A2 or D4 domains, which flank the A3 domain.

In ELISA, all point mutants and deletion mutants bound to collagen in amounts similar to wild type (WT)-vWF. In the BIAcore we found that WT-vWF has an apparent KD for collagen of 1-7 nM on a subunit base. The apparent kinetic parameters of the point mutants and deletion mutants were not significantly different from WT-vWF, except for DA2-vWF, which had a lower KD, indicating that the A2 domain somehow modulates binding of vWF to collagen type III.

Based on our results, we conclude that the amino acid residues mutated by us are not critically involved in the interaction between vWF and collagen type III, which suggests that the collagen binding site is not located on the top face of the A3 domain.

^* Present address: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands

• References

• 1 Sakariassen KS, Bolhuis PA, Sixma JJ. Human blood platelet adhesion to artery subendothelium is mediated by factor VIII-von Willebrand factor bound to the subendothelium. Nature 1979; 279: 636-8.
  CrossrefPubMedGoogle Scholar
• 2 Sixma JJ, Van Zanten GH, Huizinga EG, Van der Plas RM, Verkley M, Wu YP, Gros P, De Groot PG. Platelet adhesion to collagen: An update. Thromb Haemost 1997; 78: 434-8.
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424.
  CrossrefPubMedGoogle Scholar
• 4 Sixma JJ, Van Zanten GH, Saelman EU, Verkleij M, Lankhof H, Nieuwenhuis HK, De Groot PG. Platelet adhesion to collagen. Thromb Haemost 1995; 74: 454-9.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Rand JH. The significance of subendothelial von Willebrand Factor. Thromb Haemost 1997; 78: 445-50.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 van Genderen PJJ, Vink T, Michiels JJ, van ’t Veer MB, Sixma JJ, van Vliet HH. Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. Blood 1994; 84: 3378-84.
  PubMedGoogle Scholar
• 7 Mohri H, Hisanaga S, Mishima A, Fujimoto S, Uezono S, Okubo T. Autoantibody inhibits binding of von Willebrand factor to glycoprotein Ib and collagen in multiple myeloma. recognition sites present on the A1 loop and A3 domains of von Willebrand factor. Blood Coagul Fibrinolysis 1998; 09: 91-7.
  CrossrefPubMedGoogle Scholar
• 8 Ruggeri ZM, Ware J. von Willebrand factor. FASEB J 1993; 07: 308-16.
  CrossrefPubMedGoogle Scholar
• 9 Santoro S. Preferential binding of high molecular weight forms of von Willebrand factor to fibrillar collagen. Biochim Biophys Acta 1983; 756: 123-6.
  CrossrefPubMedGoogle Scholar
• 10 Martin SE, Marder VJ, Francis CW, Barlow GH. Structural studies on the functional heterogeneity of von Willebrand protein polymers. Blood 1981; 57: 313-23.
  PubMedGoogle Scholar
• 11 Verweij CL, Diergaarde P, Hart M, Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein, considerable larger than the mature vWF subunit. EMBO J 1986; 05: 1839-47.
  PubMedGoogle Scholar
• 12 Meitinger T, Meindl A, Bork P, Rost B, Sander C, Haasemann M, Murken J. Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure. Nat Genet 1993; 05: 376-80.
  CrossrefPubMedGoogle Scholar
• 13 Girma J-P, Chopek MW, Titani K, Davie EW. Limited proteolysis of human von Willebrand factor by Staphylococcus aureus V-8 protease: Isolation and partial characterization of a platelet-binding domain. Biochemistry 1986; 25: 3156-63.
  CrossrefPubMedGoogle Scholar
• 14 Voorberg J, Fontijn R, Calafat J, Janssen H, van Mourik JA, Pannekoek H. Assembly and routing of von Willebrand factor variants: The requirements for disulfide-linked dimerization reside within the carboxy-terminal 151 amino acids. Journal of Cell Biology 1991; 113: 195-205.
  CrossrefPubMedGoogle Scholar
• 15 Sixma JJ, Schiphorst ME, Verweij CL, Pannekoek H. Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin. Eur J Biochem 1991; 196: 369-75.
  CrossrefPubMedGoogle Scholar
• 16 Lankhof H, Wu Y-P, Vink T, Schiphorst ME, Zerwes H-G, De Groot PG, Sixma JJ, Wu YP, Zerwes HG. Role of the glycoprotein Ib-binding A1 repeat and the RGD sequence in platelet adhesion to human recombinant von Willebrand factor. Blood 1995; 86: 1035-42.
  PubMedGoogle Scholar
• 17 Lankhof H, Damas C, Schiphorst ME, IJsseldijk MJW, Bracke M, Furlan M, Tsai HM, De Groot PG, Sixma JJ, Vink T. von Willebrand factor without the A2 domain is resistant to proteolysis. Thromb Haemost 1997; 77: 1008-13.
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Lankhof H, Van Hoeij M, Schiphorst ME, Bracke M, Wu YP, IJsseldijk MJ, Vink T, De Groot PG, Sixma JJ. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75: 950-8.
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Colombatti A, Bonaldo P. The superfamily of proteins with von Willebrand factor type A-like domains: One theme common to components of extracellular matrix, hemostasis, cellular adhesion, and defense mechanisms. Blood 1991; 77: 2305-15.
  PubMedGoogle Scholar
• 20 Bork P, Rohde K. More von Willebrand factor type A domains? Sequence similarities with malaria thrombospondin-related anonymous protein, dihydropyridine-sensitive calcium channel and inter-α-trypsin inhibitor. Biochemical Journal 1991; 279: 908-10.
  CrossrefPubMedGoogle Scholar
• 21 Perkins SJ, Smith KF, Williams SC, Harris PI, Chapman D, Sim RB. The secondary structure of the von Willebrand factor type A domain in factor B of human complement by Fourier transform infrared spectroscopy. Its occurrence in collagen types VI, VII, XII and XIV, the integrins and other proteins by averaged structure predictions. J Mol Biol 1994; 238: 104-19.
  CrossrefPubMedGoogle Scholar
• 22 Michishita M, Videm V, Arnaout MA. A novel divalent cation-binding site in the A domain of the beta 2 integrin CR3 (CD11b/CD18) is essential for ligand binding. Cell 1993; 72: 857-67.
  CrossrefPubMedGoogle Scholar
• 23 Lee JO, Rieu P, Arnaout MA, Liddington R. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18). Cell 1995; 80: 631-8.
  CrossrefPubMedGoogle Scholar
• 24 Calderwood DA, Tuckwell DS, Eble J, Kühn K, Humphries MJ. The integrin α1 A-domain is a ligand binding site for collagens and laminin. J Biol Chem 1997; 272: 12311-7.
  CrossrefPubMedGoogle Scholar
• 25 Staatz WD, Rajpara SM, Wayner EA, Carter WG, Santoro SA. The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg⁺⁺-dependent adhesion of platelets to collagen. Journal of Cell Biology 1989; 108: 1917-24.
  CrossrefPubMedGoogle Scholar
• 26 Tuckwell DS, Reid KBM, Barnes MJ, Humphries MJ. The A-domain of integrin α2 binds specifically to a range of collagens but is not a general receptor for the collagenous motif. Eur J Biochem 1996; 241: 732-9.
  CrossrefPubMedGoogle Scholar
• 27 Garnotel R, Monboisse JC, Randoux A, Haye B, Borel JP. The binding of type I collagen to lymphocyte function-associated antigen (LFA) 1 integrin triggers the respiratory burst of human polymorphonuclear neutrophils. Role of calcium signaling and tyrosine phosphorylation of LFA 1. J Biol Chem 1995; 270: 27495-503.
  CrossrefPubMedGoogle Scholar
• 28 Huizinga EG, Van der Plas RM, Kroon J, Sixma JJ, Gros P. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure 1997; 05: 1147-56.
  CrossrefPubMedGoogle Scholar
• 29 Bockenstedt P, McDonagh J, Handlin RI. Binding and covalent crosslinking of purified von Willebrand factor to native monomeric collagen. J Clin Invest 1986; 78: 551-6.
  CrossrefPubMedGoogle Scholar
• 30 Bienkowska J, Cruz M, Atiemo A, Handin R, Liddington R. The von Willebrand factor A3 domain does not contain a metal ion-dependent adhesion site motif. J Biol Chem 1997; 272: 25162-7.
  CrossrefPubMedGoogle Scholar
• 31 Fitzsimmons CM, Cockburn CG, Hornsey V, Prowse CV, Barnes MJ. The interaction of von Willebrand factor (vWF) with collagen: Investigation of vWF-binding sites in the collagen molecule. Thromb Haemost 1988; 59: 186-92.
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Cruz MA, Bienkowska J, Mato A, Liddington R, Handin RI. Identification of the collagen binding site in the vWF-A3 domain by molecular structure and site-specific mutagenesis. Blood. 1997 90. 23a (abstr.).
  PubMedGoogle Scholar
• 33 Sodetz JM, Pizzo SV, McKee PA. Relationship of sialic acid to function and in vivo survival of human factor VIII/von Willebrand factor protein. J Biol Chem 1977; 252: 5538.
  PubMedGoogle Scholar
• 34 Hilbert L, Gaucher C, De Romeuf C, Horellou MH, Vink T, Mazurier C. Leu 697—>Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand disease. Blood 1994; 83: 1542-50.
  PubMedGoogle Scholar
• 35 van de Ven WJM, Voorberg J, Fontijn R, Pannekoek H, van den Ouwenland AMW, van Duijnhoven HLP, Roebroek AJM, Siezen RJ. Furin is a subtilisin like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep 1990; 14: 265-75.
  CrossrefPubMedGoogle Scholar
• 36 Fischer BE, Schlokat U, Reiter M, Mundt W, Dorner F. Biochemical and functional characterization of recombinant von Willebrand factor produced on a large scale. Cell Mol Life Sci 1997; 53: 943-50.
  CrossrefPubMedGoogle Scholar
• 37 Lawrie AS, Hoser MJ, Savidge GF. Phast assessment of vWf:Ag multimeric distribution. Thromb Res 1990; 59: 369-73.
  CrossrefPubMedGoogle Scholar
• 38 Saelman EU, Nieuwenhuis HK, Hese KM, De Groot PG, Heijnen HF, Sage EH, Williams S, McKeown L, Gralnick HR, Sixma JJ. Platelet adhesion to collagen types I through VIII under conditions of stasis and flow is mediated by GPIa/IIa (alpha 2 beta 1-integrin). Blood 1994; 83: 1244-50.
  PubMedGoogle Scholar
• 39 Fagerstam LG, Frostell-Karlsson LG, Karlsson R, Persson R, Ronnberg I. J Chromatogr. 1992; 597: 397-410.
  PubMedGoogle Scholar
• 40 Sasaki T, Göhring W, Mann K, Maurer P, Hohenester E, Knäuper V, Murphy G, Timpl R. Limited cleavage of extracellular matrix protein BM-40 by matrix metalloproteinases increases its affinity for collagens. J Biol Chem 1997; 272: 9237-43.
  CrossrefPubMedGoogle Scholar
• 41 Kraulis PJ. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J Appl Cryst 1991; 24: 946-50.
  CrossrefPubMedGoogle Scholar
• 42 Shelton-Inloes BB, Titani K, Sadler JE. cDNA sequence for human von Willebrand factor reveals five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry 1986; 25: 3164-71.
  CrossrefPubMedGoogle Scholar
• 43 Obert B, Houllier A, Meyer D, Girma JP. Conformational changes in the A3 domain of von Willebrand Factor modulate the interaction of the A1 domain with Glycoprotein Ib. Blood 1999; 93: 1959-68.
  PubMedGoogle Scholar