Attribution of the various inhibitory actions of the streptococcal inhibitor of complement (SIC) to regions within the molecule

Some strains of Streptococcus pyogenes secrete a virulence factor called the streptococcal inhibitor of complement ( SIC) function. SIC is a polyfunctional protein that interacts with a number of host proteins and peptides, especially with those that are involved in host defense systems. In addition to inhibiting the complement-mediated lysis of cells, SIC inhibits lysozyme, secretory leukocyte proteinase inhibitor, and beta-defensins. SIC also binds to proteins associated with the cytoskeleton and thereby may cause cytoskeletal derangement. The SIC molecule has three distinct structural domains constituting the N-proximal short repeat region (SRR), the central long repeat region (LRR), and the C-proximal proline-rich region (PRR). To map various functions to the structural domains, we have analyzed recombinant subclones expressing various parts of SIC and elastase-generated discrete fragments of SIC for binding to various ligands and for determining their biological properties. The results demonstrate the following. ( a) SRR alone was sufficient to confer inhibition of complement function. (b) Anti-defensin and anti-lysozyme activities were mapped to the SRR plus LRR. ( c) The LRR plus PRR harbored ezrin binding activity.