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J Biol Chem, Vol. 274, Issue 22, 15336-15344, May 28, 1999

Protein GRAB of Streptococcus pyogenes Regulates Proteolysis at the Bacterial Surface by Binding ₂-Macroglobulin

Magnus Rasmussen, Hans-Peter Müller^§, and Lars Björck

From the  Department of Cell and Molecular Biology, Section for Molecular Pathogenesis, Lund University, S-221 00 Lund, Sweden and the ^§ Department of Immunology and Transfusion Medicine, Greifswald University, D-17487 Greifswald, Germany

In the molecular interplay between pathogenic microorganisms and their host, proteolytic mechanisms are believed to play a crucial role. Here we find that the important human pathogen Streptococcus pyogenes (group A Streptococcus) expresses a surface protein with high affinity (K_a = 2.0 × 10⁸ M¹) for ₂-macroglobulin (₂M), the dominating proteinase inhibitor of human plasma. The immunoglobulin-binding protein G of group C and G streptococci also contains an ₂M-binding domain and a gene encoding protein GRAB (protein G-related ₂M-binding protein) was identified in the S. pyogenes Genome Sequencing data base. The grab gene is present in most S. pyogenes strains and is well conserved. Protein GRAB has typical features of a surface-attached protein of Gram-positive bacteria. It also contains a region homologous to parts of the ₂M-binding domain of protein G and a variable number of a unique 28-amino acid-long repeat. Using Escherichia coli-produced protein GRAB and synthetic GRAB peptides, the ₂M-binding region was mapped to the NH₂-terminal part of protein GRAB, which is the region with homology to protein G. An isogenic S. pyogenes mutant lacking surface-associated protein GRAB showed no ₂M binding activity and was attenuated in virulence when injected intraperitoneally in mice. Finally, ₂M bound to the bacterial surface via protein GRAB was found to entrap and inhibit the activity of both S. pyogenes and host proteinases, thereby protecting important virulence determinants from proteolytic degradation. This regulation of proteolytic activity at the bacterial surface should affect the host-microbe relation during S. pyogenes infections.

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