Specificity of the thioester-containing reactive site of human C3 and its significance to complement activation.
The specificity of the thioester-containing site in three plasma proteins is regulated by elements of their protein structures other than the thioester bond itself. Human C4A and alpha 2-macroglobulin preferentially form amide linkages while human C3 primarily forms ester linkages with hydroxyl groups. We have examined the thioester in C3 and found evidence of strong preferences for certain carbohydrates, indications of selectivity for specific positions on those carbohydrates and a preference for terminal sugars in polysaccharides. A testable set of rules are derived from these findings which predict preferred attachment sites on polysaccharides. A computer model of the effect of different reactivities on activation of the alternative pathway of complement suggested that organisms might greatly alter their susceptibility to complement with small changes in carbohydrate structure. While a random selection of 20 biological particles showed no correlation between activation and C3b attachment efficiency, subsets of related organisms differing primarily in their surface polysaccharide exhibited stronger correlations. The strongest correlation occurred in a series of the yeasts (Cryptococcus neoformans) possessing capsular polysaccharides with one, two, three or four branching xylose sugars per repeating unit. These organisms exhibited capture efficiencies for metastable C3b from 12% (one-xylose strain) to 41% (four-xylose strain).
Sahu
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Department of Biochemistry, University of Texas Health Science Center, Tyler 75710.
Kozel
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Pangburn
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D000438:Alcohols / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002852:Chromatography, Ion Exchange; D003179:Complement C3b / Q000737:chemistry / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D003198:Computer Simulation; D003455:Cryptococcus neoformans / Q000276:immunology; D006801:Humans; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D011135:Polysaccharides, Bacterial / Q000737:chemistry / Q000378:metabolism
D000438:Alcohols; D011134:Polysaccharides; D011135:Polysaccharides, Bacterial; D003179:Complement C3b