Streptococcal IgA-binding proteins bind in the C alpha 2-C alpha 3 interdomain region and inhibit binding of IgA to human CD89

Certain pathogenic bacteria express surface proteins that bind to the Fc pa rt of human TgA or IgG. These bacterial proteins are important as immunoche mical tools and model systems, but their biological function is still uncle ar. Here, we describe studies of three streptococcal proteins that bind IgA : the Sir22 and Arp4 proteins of Streptococcus pyogenes and the unrelated b eta protein of group B streptococcus. Analysis of IgA domain swap and point mutants indicated that two loops at the C alpha2/C alpha3 domain interface are critical for binding of the streptococcal proteins. This region is als o used in binding the human IgA receptor CD89, an important mediator of IgA effector function. In agreement with this finding, the three IgA-binding p roteins and a 50-residue IgA-binding peptide derived from Sir22 blocked the ability of IgA to bind CD89. Further, the Arp4 protein inhibited the abili ty of IgA to trigger a neutrophil respiratory burst via CD89. Thus, we have identified residues on IgA-Fc that play a key role in binding of different streptococcal IgA-binding proteins, and we have identified a mechanism by which a bacterial IgA-binding protein may interfere with TgA effector funct ion.