Abstract
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.
Highlights
Some strains of Streptococcus pyogenes secrete a major protein, called “streptococcal inhibitor of complement” (SIC),1 which was originally identified as an inhibitor of the membrane attack complex (MAC) (1)
It inhibits the antimicrobial activity of lysozyme, secretory leukocyte proteinase inhibitor (SLPI), ␣- and -defensins, and LL-37, which are all components of the innate immune system (5–7)
The sequence of SIC revealed three distinct regions (1, 3, 14) (Fig. 1) as follows: (a) an N-proximal, tryptophan-rich, short repeat region (SRR) called the DWS repeat region; (b) the central long repeat region (LRR); and (c) a C-proximal prolinerich region (PRR). The role of these regions in the diverse biochemical/biological functions outlined above is unknown, some preliminary binding data using proteolytic fragments of the SIC protein show that only a fragment comprising most of the SRR plus part of the LRR binds to the -defensins and SLPI (7, 15)
Summary
Bacterial Strains, DNA, Peptides, and Antibodies—S. pyogenes 2031, an M1 serotype, was used to obtain clones of the sic gene and portions corresponding to one or more of structural domains of the protein. Streptococcus was grown in Todd Hewitt broth (Oxoid) supplemented with neopeptone. DNA manipulations and sequencing were as described previously (2, 6).
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