Polyanion-induced self-association of complement factor H: possible mechanism of host protection from an innate immune system (53.11)

Abstract

Abstract Factor H is the primary soluble regulator of activation of the complement alternative pathway. It prevents activation of complement on host cells and tissues upon association with surface polyanions such as sialic acids, heparin and other glycosaminoglycans. We now show that interaction with polyanions causes self-association forming tetramers of the 155,000 dalton glycosylated protein. Monomeric human factor H is composed of twenty homologous CCP domains and in its extended form it exists as a flexible protein approximately 380 to 730 angstroms in length and 35 angstroms in width. Due to its extended shape, it exhibits an apparent size of 330,000 daltons, relative to globular standards, during gel filtration in the absence of polyanions. In the presence of dextran sulfate (5,000 daltons) its apparent Mr was found to be 1,400,000 daltons by gel filtration. Similar effects were seen with heparin. Sedimentation equilibrium analysis by analytical ultracentrifugation indicated a monomer Mr of 163,000 in the absence of polyanions and a tetramer of 607,000 Mr in the presence of less that a two-fold molar excess of dextran sulfate. The results suggest that recognition of polyanionic markers on host cells and tissues by factor H and the resulting inhibition of complement activation may involve formation of dimers and tetramers of factor H. Support: NIH grant DK-35081, NIH grant HL-073804 and AHA grant 0265178Y.