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Critical Role of the C-Terminal Domains of Factor H in Regulating Complement Activation at Cell Surfaces¹

Viviana P. Ferreira^*, Andrew P. Herbert, Henry G. Hocking, Paul N. Barlow and Michael K. Pangburn^2,*

^* Department of Biochemistry, Center for Biomedical Research, University of Texas, Health Science Center, Tyler, TX 75708; and Edinburgh Biomolecular Nuclear Magnetic Resonance Unit, University of Edinburgh, Edinburgh, United Kingdom

The plasma protein factor H primarily controls the activation of the alternative pathway of complement. The C-terminal of factor H is known to be involved in protection of host cells from complement attack. In the present study, we show that domains 19–20 alone are capable of discriminating between host-like and complement-activating cells. Furthermore, although factor H possesses three binding sites for C3b, binding to cell-bound C3b can be almost completely inhibited by the single site located in domains 19–20. All of the regulatory activities of factor H are expressed by the N-terminal four domains, but these activities toward cell-bound C3b are inhibited by isolated recombinant domains 19–20 (rH 19–20). Direct competition with the N-terminal site is unlikely to explain this because regulation of fluid phase C3b is unaffected by domains 19–20. Finally, we show that addition of isolated rH 19–20 to normal human serum leads to aggressive complement-mediated lysis of normally nonactivating sheep erythrocytes and moderate lysis of human erythrocytes, which possess membrane-bound regulators of complement. Taken together, the results highlight the importance of the cell surface protective functions exhibited by factor H compared with other complement regulatory proteins. The results may also explain why atypical hemolytic uremic syndrome patients with mutations affecting domains 19–20 can maintain complement homeostasis in plasma while their complement system attacks erythrocytes, platelets, endothelial cells, and kidney tissue.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grant DK-35081.

² Address correspondence and reprint requests to Dr. Michael K. Pangburn, Department of Biochemistry, University of Texas Health Science Center, Tyler, TX 75708. E-mail address: michael.pangburn{at}uthct.edu

³ Abbreviations used in this paper: aHUS, atypical hemolytic uremic syndrome; CCP, complement control protein domain; rH 19–20, recombinant domains 19–20 of factor H; VBS, veronal-buffered saline; GVB, gelatin-VBS; GVBE, GVB-EDTA; DGVB, dextrose-GVB; E_S, E_R, and E_H, sheep, rabbit, and human erythrocytes, respectively; E_SC3b and E_RC3b, C3b-coated erythrocyte; NHS, normal human sera; CRP, complement regulatory protein.

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