Our goal is to better understand how the terminal complement proteins damage cell membranes and how cells protect themselves from such complement damage. Complement-induced membrane damage is mediated by the terminal complement proteins C5- C9. When activated, these terminal complement proteins form transmembrane channels in the membrane of nearby cells. We found that complement channels are not formed randomly but within membrane domains. If complement preferentially localizes to membrane domains, a receptor must be within the domains for one or more of the terminal complement proteins. Aterminal complement proteinss the initial interaction between the terminal complement proteins and the membrane occurs with C5b6, this complex is the most likely ligand of such a receptor.
We identified these molecules on the erythrocyte surface that the terminal complement proteins bind to: anionic phospholipids, gangliosides, and sialic acid present on glycophorin. We have also shown that the stage of complement channel formation at which this interaction occurs is at the stage of C5b6 binding to the membrane. The focus of our research now is to understand how C5b6 interacts with these anionic molecules and to use this information to develop soluble inhibitors of the terminal complement proteins. This work is clinically important because the terminal complement proteins are a primary focus in the destruction of xenogeneic grafts, i.e., grafts between species. Inhibitors such as the ones we are developing may increase the ability of these xenografts to be used in transplantation.
