Interaction of fucoidan with the proteins of the complement classical pathway.
Fucoidan inhibits complement by mechanisms that so far remain to be unraveled, and the objective of this work was to delineate the mode of inhibition by this sulfated polysaccharide. For that purpose, low molecular weight fractions of algal (Ascophyllum nodosum) fucoidan containing the disaccharide unit [-->3)-alpha-L-Fuc(2SO3(-))-(1-->4)-alpha-L-Fuc(2,3diSO3(-))-(1-->](n) have been studied. Gel co-affinity electrophoresis and a new affinity capillary electrophoresis (ACE) method have been implemented to characterize fucoidan-complement protein complexes. Fucoidan binds C1q, likely to its collagen-like region through interactions involving lysine residues, and then prevents the association of the C1r(2)-C1s(2) subunit, required to form the fully active C1. In addition to C1q, fucoidan forms a complex with the protein C4 as observed by ACE. The fucoidan inhibits the first steps of the classical pathway activation that is of relevance in view of the proinflammatory effects of the subsequent products of the cascade. This study shows that a high level of inhibitory activity can be achieved with low molecular weight carbohydrate molecules and that the potential applicability of fucoidan oligosaccharides for therapeutic complement inhibition is worthy of consideration.
D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D003167:Complement Activation; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism*; D015922:Complement C1q / Q000276:immunology / Q000378:metabolism*; D015923:Complement C1r / Q000378:metabolism; D003173:Complement C1s / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D009097:Multienzyme Complexes; D000459:Phaeophyceae / Q000737:chemistry; D011134:Polysaccharides / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D003174:Complement C1 Inactivator Proteins; D003181:Complement C4; D009097:Multienzyme Complexes; D011134:Polysaccharides; D013463:Sulfuric Acid Esters; D015922:Complement C1q; C007789:fucoidan; D015923:Complement C1r; D003173:Complement C1s; D008239:Lysine