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CC BY 4.0 · TH Open 2018; 02(03): e338-e345
DOI: 10.1055/s-0038-1672189
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Complement Component C3 Binds to the A3 Domain of von Willebrand Factor

Jennifer G. Nolasco
1   Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
,
Leticia H. Nolasco
2   Department of Bioengineering, Rice University, Houston, Texas, United States
,
Qi Da
1   Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
3   Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas, United States
,
Sonya Cirlos
1   Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
3   Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas, United States
,
Zaverio M. Ruggeri
4   Department of Molecular Medicine, MERU-Roon Research Center on Vascular Biology, The Scripps Research Institute, La Jolla, California, United States
,
Joel L. Moake
2   Department of Bioengineering, Rice University, Houston, Texas, United States
,
Miguel A. Cruz
1   Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
3   Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, Texas, United States
› Author Affiliations Funding This work was supported by grants from the Mary R. Gibson Foundation, the Mabel and Everett Hinkson Memorial Fund, the Alkek Foundation, NIH/NIGMS GM-112806, and NIH/NINDS NS-094280.
Further Information

Publication History

23 May 2018

16 August 2018

Publication Date:
26 September 2018 (online)

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Abstract

von Willebrand factor (VWF) is a multimeric protein composed of monomeric subunits (∼280 kD) linked by disulfide bonds. During hemostasis and thrombosis, ultralarge (UL) VWF (ULVWF) multimers initiate platelet adhesion. In vitro, human C3 binds to ULVWF multimeric strings secreted by and anchored to human endothelial cell to promote the assembly and activation of C3 convertase (C3bBb) and C5 convertase (C3bBbC3b) of the alternative complement pathway (AP). The purified and soluble C3 avidly binds to recombinant human VWF A1A2A3, as well as the recombinant isolated human VWF A3 domain. Notably, the binding of soluble human ULVWF multimers to purified human C3 was blocked by addition of a monovalent Fab fragment antibody to the VWF A3 domain. We conclude that the A3 domain in VWF/ULVWF contains a docking site for C3. In contrast, purified human C4, an essential component of the classical and lectin complement pathways, binds to soluble, isolated A1, but not to ULVWF strings secreted by and anchored to endothelial cells. Our findings should facilitate the design of new therapeutic agents to suppress the initiation of the AP on ULVWF multimeric strings during thrombotic and inflammatory disorders.

Keywords

complement component C3 - von Willebrand factor - alternative complement pathway - thrombosis - inflammation

Authors' Contributions

J.G.N., Q.D., S.C., and L.H.N. performed experiments, collected and interpreted data, and helped in writing the manuscript; Z.M.R generated the monoclonal antibody against the A3 domain, and helped write the paper; J.L.M. designed experiments, analyzed data, and helped write the paper; M.A.C. contributed ideas for experiments, reagents, and helped write the paper.


Notes

The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government.


 

  • References

  • 1 Ruggeri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost 1997; 78 (01) 611-616
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Dong JF, Moake JL, Nolasco L. , et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100 (12) 4033-4039
    CrossrefPubMedGoogle Scholar
  • 3 Turner NA, Nolasco L, Ruggeri ZM, Moake JL. Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 2009; 114 (24) 5102-5111
    CrossrefPubMedGoogle Scholar
  • 4 Turner NA, Moake J. Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis. PLoS One 2013; 8 (03) e59372
    CrossrefPubMedGoogle Scholar
  • 5 Chen ZA, Pellarin R, Fischer L. , et al. Structure of complement C3(H2O) revealed by quantitative cross-linking/mass spectrometry and modeling. Mol Cell Proteomics 2016; 15 (08) 2730-2743
    CrossrefPubMedGoogle Scholar
  • 6 Andersson J, Ekdahl KN, Larsson R, Nilsson UR, Nilsson B. C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase. J Immunol 2002; 168 (11) 5786-5791
    CrossrefPubMedGoogle Scholar
  • 7 Roth GJ, Titani K, Hoyer LW, Hickey MJ. Localization of binding sites within human von Willebrand factor for monomeric type III collagen. Biochemistry 1986; 25 (26) 8357-8361
    CrossrefPubMedGoogle Scholar
  • 8 Auton M, Sowa KE, Smith SM, Sedlák E, Vijayan KV, Cruz MA. Destabilization of the A1 domain in von Willebrand factor dissociates the A1A2A3 tri-domain and provokes spontaneous binding to glycoprotein Ibalpha and platelet activation under shear stress. J Biol Chem 2010; 285 (30) 22831-22839
    CrossrefPubMedGoogle Scholar
  • 9 Lo NC, Turner NA, Cruz MA, Moake J. Interaction of Shiga toxin with the A-domains and multimers of von Willebrand Factor. J Biol Chem 2013; 288 (46) 33118-33123
    CrossrefPubMedGoogle Scholar
  • 10 Arya M, Anvari B, Romo GM. , et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 2002; 99 (11) 3971-3977
    CrossrefPubMedGoogle Scholar
  • 11 Kumar RA, Moake JL, Nolasco L. , et al. Enhanced platelet adhesion and aggregation by endothelial cell-derived unusually large multimers of von Willebrand factor. Biorheology 2006; 43 (05) 681-691
    PubMedGoogle Scholar
  • 12 Cruz MA, Chen J, Whitelock JL, Morales LD, López JA. The platelet glycoprotein Ib-von Willebrand factor interaction activates the collagen receptor alpha2beta1 to bind collagen: activation-dependent conformational change of the alpha2-I domain. Blood 2005; 105 (05) 1986-1991
    CrossrefPubMedGoogle Scholar
  • 13 Morales LD, Martin C, Cruz MA. The interaction of von Willebrand factor-A1 domain with collagen: mutation G1324S (type 2M von Willebrand disease) impairs the conformational change in A1 domain induced by collagen. J Thromb Haemost 2006; 4 (02) 417-425
    CrossrefPubMedGoogle Scholar
  • 14 Law SK, Levine RP. Interaction between the third complement protein and cell surface macromolecules. Proc Natl Acad Sci U S A 1977; 74 (07) 2701-2705
    CrossrefPubMedGoogle Scholar
  • 15 Pangburn MK, Ferreira VP, Cortes C. Discrimination between host and pathogens by the complement system. Vaccine 2008; 26 (Suppl. 08) I15-I21
    CrossrefPubMedGoogle Scholar
  • 16 Law SK, Dodds AW. The internal thioester and the covalent binding properties of the complement proteins C3 and C4. Protein Sci 1997; 6 (02) 263-274
    PubMedGoogle Scholar
  • 17 Schreiber RD, Pangburn MK, Lesavre PH, Müller-Eberhard HJ. Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins. Proc Natl Acad Sci U S A 1978; 75 (08) 3948-3952
    CrossrefPubMedGoogle Scholar
  • 18 Fearon DT, Austen KF, Ruddy S. Formation of a hemolytically active cellular intermediate by the interaction between properdin factors B and D and the activated third component of complement. J Exp Med 1973; 138 (06) 1305-1313
    CrossrefPubMedGoogle Scholar
  • 19 Bettoni S, Galbusera M, Gastoldi S. , et al. Interaction between multimeric von Willebrand factor and complement: a fresh look to the pathophysiology of microvascular thrombosis. J Immunol 2017; 199 (03) 1021-1040
    CrossrefPubMedGoogle Scholar
  • 20 Lankhof H, van Hoeij M, Schiphorst ME. , et al. A3 domain is essential for interaction of von Willebrand factor with collagen type III. Thromb Haemost 1996; 75 (06) 950-958
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Daidone V, Saga G, Barbon G. , et al. The p.R1819_C1948delinsS mutation makes von Willebrand factor ADAMTS13-resistant and reduces its collagen-binding capacity. Br J Haematol 2015; 170 (04) 564-573
    CrossrefPubMedGoogle Scholar
  • 22 Legendre P, Navarrete AM, Rayes J. , et al. Mutations in the A3 domain of von Willebrand factor inducing combined qualitative and quantitative defects in the protein. Blood 2013; 121 (11) 2135-2143
    CrossrefPubMedGoogle Scholar
  • 23 Wang A, Liu F, Dong N. , et al. Thrombospondin-1 and ADAMTS13 competitively bind to VWF A2 and A3 domains in vitro. Thromb Res 2010; 126 (04) e260-e265
    CrossrefPubMedGoogle Scholar
  • 24 Majerus EM, Anderson PJ, Sadler JE. Binding of ADAMTS13 to von Willebrand factor. J Biol Chem 2005; 280 (23) 21773-21778
    CrossrefPubMedGoogle Scholar
  • 25 Harris CL, Abbott RJ, Smith RA, Morgan BP, Lea SM. Molecular dissection of interactions between components of the alternative pathway of complement and decay accelerating factor (CD55). J Biol Chem 2005; 280 (04) 2569-2578
    CrossrefPubMedGoogle Scholar
  • 26 Forneris F, Ricklin D, Wu J. , et al. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 2010; 330 (6012): 1816-1820
    CrossrefPubMedGoogle Scholar
  • 27 Hinshelwood J, Spencer DI, Edwards YJ, Perkins SJ. Identification of the C3b binding site in a recombinant vWF-A domain of complement factor B by surface-enhanced laser desorption-ionisation affinity mass spectrometry and homology modelling: implications for the activity of factor B. J Mol Biol 1999; 294 (02) 587-599
    CrossrefPubMedGoogle Scholar
  • 28 Coulpier M, Andreev S, Lemercier C. , et al. Activation of the endothelium by IL-1 alpha and glucocorticoids results in major increase of complement C3 and factor B production and generation of C3a. Clin Exp Immunol 1995; 101 (01) 142-149
    PubMedGoogle Scholar
  • 29 Hoie EB, McGuire TR, Leuschen PM, Zach TL. Pentoxifylline inhibits tumor necrosis factor-alpha induced synthesis of complement component C3 in human endothelial cells. Biol Pharm Bull 2004; 27 (10) 1670-1673
    CrossrefPubMedGoogle Scholar
  • 30 Auton M, Cruz MA, Moake J. Conformational stability and domain unfolding of the Von Willebrand factor A domains. J Mol Biol 2007; 366 (03) 986-1000
    CrossrefPubMedGoogle Scholar
  • 31 Sahu A, Pangburn MK. Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3. Biochem Pharmacol 1996; 51 (06) 797-804
    CrossrefPubMedGoogle Scholar
  • 32 Sahu A, Rawal N, Pangburn MK. Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b. Biochem Pharmacol 1999; 57 (12) 1439-1446
    CrossrefPubMedGoogle Scholar
  • 33 Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: is C3 a contact-activated protein?. Immunobiology 2012; 217 (11) 1106-1110
    CrossrefPubMedGoogle Scholar
  • 34 Turner N, Nolasco L, Nolasco J, Sartain S, Moake J. Thrombotic microangiopathies and the linkage between von Willebrand factor and the alternative complement pathway. Semin Thromb Hemost 2014; 40 (05) 544-550
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Cruz MA, Handin RI, Wise RJ. The interaction of the von Willebrand factor-A1 domain with platelet glycoprotein Ib/IX. The role of glycosylation and disulfide bonding in a monomeric recombinant A1 domain protein. J Biol Chem 1993; 268 (28) 21238-21245
    PubMedGoogle Scholar
  • 36 Aponte-Santamaría C, Huck V, Posch S. , et al. Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions. Biophys J 2015; 108 (09) 2312-2321
    CrossrefPubMedGoogle Scholar
  • 37 Martin C, Morales LD, Cruz MA. Purified A2 domain of von Willebrand factor binds to the active conformation of von Willebrand factor and blocks the interaction with platelet glycoprotein Ibalpha. J Thromb Haemost 2007; 5 (07) 1363-1370
    CrossrefPubMedGoogle Scholar