%0 Journal Article
%T Molecular Interactions between Complement Factor H and Its Heparin and Heparan Sulfate Ligands
%A Stephen J. Perkins
%J Frontiers in Immunology
%D 2014
%I Frontiers Media
%R 10.3389/fimmu.2014.00126
%X Complement factor H (CFH) is the major regulator of the central complement protein C3b in the alternative pathway of complement activation. A molecular view of the CFH interaction with native heparan sulfate (HS) is central for understanding the mechanism of how surface-bound CFH interacts with C3b bound to host cell surfaces. HS is composed of sulfated heparin-like S-regions that alternate with desulfated NA-regions. Solution structural studies of heparin (equivalent to the S-regions) and desulfated HS (the NA-regions) by scattering and ultracentrifugation showed that each structure was mostly extended and partially bent, but with greater bending and flexibility in the NA-regions compared to the S-regions. Their solution structures have been deposited in the Protein Data Bank. The largest HS oligosaccharides showed more bent and flexible structures than those for heparin. A folded-back domain structure for the solution structure of the 20 domains in CFH was determined likewise. CFH binds to the S-regions but less so to the NA-regions of HS. The bivalent interaction of CFH¨Cheparin was observed by ultracentrifugation, and binding studies of CFH fragments with heparin-coated sensor chips. In common with other CFH interactions with its physiological and pathophysiological ligands, the CFH¨Cheparin and CFH¨CC3b interactions have moderate micromolar dissociation constants KD, meaning that these complexes do not fully form in vivo. The combination of the solution structures and binding studies indicated a two-site interaction model of CFH with heparin at cell surfaces. By this, the bivalent binding of CFH to a cell surface is co-operative. Defective interactions at either of the two independent CFH¨Cheparin sites reduce the CFH interaction with surface-bound C3b and lead to immune disorders.
%K analytical ultracentrifugation
%K surface plasmon resonance
%K X-ray scattering
%K complement factor H
%K heparin
%K heparan sulfate
%U http://www.frontiersin.org/Journal/10.3389/fimmu.2014.00126/abstract