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)

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.

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.