Regulation of alternative pathway complement activation by glycosaminoglycans: specificity of the polyanion binding site on factor H.
The discrimination between activators and nonactivators of the alternative pathway of complement depends on the affinity of the control factor H for C3b molecules covalently associated with the target. The affinity of factor H for the C3b-target complex is regulated by a positively charged site at or near the 13th short consensus repeat (SCR) domain of factor H. In this study we have analyzed the ability of different glycosaminoglycans and other negatively charged macromolecules to interact with the factor H polyanion recognition site and to enhance binding of H to the C3b-target complex. Strongest enhancement of factor H binding to zymosan-C3b was observed by the highly sulphated glycoconjugates dextran sulphate (m.w. = 5,000), heparin, chondroitin sulphate A and carrageenan (types III and IV). DNA also enhanced H binding. Removal of N-linked sulphates or reduction of the size of heparin decreased its enhancing effect on H binding. Little or no effect was seen with chondroitin sulphate C, keratan sulphate, hyaluronic acid, colominic acid (bacterial polysialic acid) or negatively charged polypeptides. The results show that the interaction of the polyanion binding site on factor H with glycosaminoglycans depends upon the number, orientation and polymeric arrangement of sulphate groups and suggest that most, but not all, sulphated glycosaminoglycans participate in the protection of host tissues from complement damage by promoting inactivation of tissue-bound C3b.
Meri
S
S
Department of Bacteriology and Immunology, University of Helsinki, Finland.
Pangburn
M K
MK
D000838:Anions; D001665:Binding Sites; D002351:Carrageenan / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000494:pharmacology; D003176:Complement C3 / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism*; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D016264:Dextran Sulfate / Q000494:pharmacology; D006001:Glycoconjugates / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D007632:Keratan Sulfate / Q000494:pharmacology; D007700:Kinetics
D000838:Anions; D002351:Carrageenan; D002809:Chondroitin Sulfates; D003176:Complement C3; D003179:Complement C3b; D017242:Complement Factor H; D016264:Dextran Sulfate; D006001:Glycoconjugates; D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D006820:Hyaluronic Acid; D007632:Keratan Sulfate; C493495:CFH protein, human