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JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
A cluster of positively charged amino acids in the alpha-chain of C4b-binding protein (C4BP) is pivotal for the regulation of the complement system and the interaction with bacteria.
C4b-binding protein (C4BP) is a potent inhibitor of the classical pathway of complement. Structural analysis of our 3D model of the C4BP alpha-chain suggested that a cluster of positively charged amino acids at the interface between complement control protein (CCP) modules 1 and 2 could be involved in ligand binding. Nine C4BP mutants, where the positively charged amino acids were changed to glutamines, were expressed. We found that all of these displayed lower apparent affinity for C4b and that the site was also a specific heparin-binding site. The mutants demonstrated decreased ability to serve as factor I cofactors in a degradation of C4b. Also, their capacity to prevent the assembly of C3-convertase and to accelerate its decay were decreased. In conclusion, we found a binding site on C4BP that is functionally important for the regulation of C3-convertase. Many strains of Streptococcus pyogenes bind C4BP, via surface M proteins, which plays an important role in pathogenesis. Using the set of C4BP mutants we identified a key recognition surface for M proteins which overlaps with the C4b-binding site. The analysis of all mutants and inhibition with monoclonal antibodies indicated that the binding sites for C4b and M proteins are only overlapping but not identical. Furthermore, we found that the molecular mechanisms involved in these two interactions differ, since the binding between M proteins and C4BP is relatively insensitive to salt in contrast to the C4BP-C4b-binding. We suggest that binding between C4b and C4BP is governed mostly by electrostatic interactions, while additional non-covalent forces cause tight binding of C4BP to streptococcal M proteins.
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