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*
Department of Clinical Chemistry, Lund University, University Hospital Malmö, Malmö, Sweden; and
Department of Laboratory Medicine, Lund University, Lund, Sweden
Many strains of Streptococcus pyogenes bind
C4b-binding protein (C4BP), an inhibitor of complement activation. The
binding is mediated by surface M proteins in a fashion that has been
suggested to mimic the binding of C4b. We have previously shown that a
positively charged cluster at the interface between complement control
protein domains 1 and 2 of C4BP 
-chain is crucial for the C4b-C4BP
interaction. To extend this observation, and to investigate the
interaction with M proteins, we constructed and characterized a total
of nine mutants of C4BP. We identified a key recognition surface for M
proteins that overlaps with the C4b binding site because substitution
of R64 and H67 by Gln dramatically reduces binding to both ligands.
However, the analysis of all mutants indicates that the binding sites
for C4b and M proteins are only overlapping, but not identical.
Furthermore, M proteins were able to displace C4BP from immobilized
C4b, whereas C4b only weakly affected binding of C4BP to immobilized M
proteins. We found that the molecular mechanisms involved in these two
interactions differ because the binding between M proteins and C4BP is
relatively insensitive to salt in contrast to the C4BP-C4b binding. In
addition, six mAbs directed against the -chain interfered with
C4b-C4BP interaction, whereas only two of them efficiently inhibited
binding of C4BP to M proteins. Collectively, our results suggest that
binding between C4b and C4BP is governed mostly by electrostatic
interactions, while additional noncovalent forces cause tight binding
of C4BP to streptococcal M proteins.
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