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* Department of Biochemistry, Center for Biomedical Research, University of Texas Health Science Center, Tyler, TX 75708; and
Department of Biological Sciences, Texas A&M University, Texarkana, TX 75505
Factor H is the primary soluble regulator of activation of the alternative pathway of complement. It prevents activation of complement on host cells and tissues upon association with C3b and surface polyanions such as sialic acids, heparin, and other glycosaminoglycans. Here we show that interaction with polyanions causes self-association forming tetramers of the 155,000 Da glycosylated protein. Monomeric human factor H is an extended flexible protein that exhibits an apparent size of 330,000 Da, relative to globular standards, during gel filtration chromatography in the absence of polyanions. In the presence of dextran sulfate (5000 Da) or heparin an intermediate species of apparent m.w. 700,000 and a limit species of m.w. 1,400,000 were observed by gel filtration. Sedimentation equilibrium analysis by analytical ultracentrifugation indicated a monomer Mr of 163,000 in the absence of polyanions and a Mr of 607,000, corresponding to a tetramer, in the presence of less than a 2-fold molar excess of dextran sulfate. Increasing concentrations of dextran sulfate increased binding of factor H to zymosan-C3b 4.5-fold. This result was accompanied by an increase in both the decay accelerating and cofactor activity of factor H on these cells. An expressed fragment encompassing the C-terminal polyanion binding site (complement control protein domains 18–20) also exhibited polyanion-induced self-association, suggesting that the C-terminal ends of factor H mediate self-association. The results suggest that recognition of polyanionic markers on host cells and tissues by factor H, and the resulting regulation of complement activation, may involve formation of dimers and tetramers of factor H.
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 work was supported by Grants DK-35081 (to M.K.P.) and HL-073804 (to N.R.) from the National Institutes of Health and by Grants 0265178Y (to N.R.) and 0735101N (to V.P.F.) from the American Heart Association.
2 Address correspondence and reprint requests to Dr. Michael K. Pangburn, Department of Biochemistry, Center for Biomedical Research, University of Texas Health Science Center, 11937 US Highway 271, 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; GVB, veronal-buffered saline containing 0.1% gelatin; NMR, nuclear magnetic resonance.
This article has been cited by other articles:
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  V. P. Ferreira, A. P. Herbert, C. Cortes, K. A. McKee, B. S. Blaum, S. T. Esswein, D. Uhrin, P. N. Barlow, M. K. Pangburn, and D. Kavanagh The Binding of Factor H to a Complex of Physiological Polyanions and C3b on Cells Is Impaired in Atypical Hemolytic Uremic Syndrome J. Immunol., June 1, 2009; 182(11): 7009 - 7018. [Abstract] [Full Text] [PDF]
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