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 ؋ 10 8 M ؊1 ) for ␣ 2 -macroglobulin (␣ 2 M), the dominating proteinase inhibitor of human plasma. The immunoglobulin-binding protein G of group C and G streptococci also contains an ␣ 2 M-binding domain and a gene encoding protein GRAB (protein G-related ␣ 2 M-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 surfaceattached protein of Gram-positive bacteria. It also contains a region homologous to parts of the ␣ 2 M-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 ␣ 2 M-binding region was mapped to the NH 2 -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 ␣ 2 M binding activity and was attenuated in virulence when injected intraperitoneally in mice. Finally, ␣ 2 M 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.Streptococcus pyogenes is an important human pathogen that causes a variety of diseases such as pharyngitis, impetigo, scarlatina, and erysipelas. More severe infections caused by this organism are necrotizing fasciitis and streptococcal toxic shock-like syndrome. S. pyogenes binds several human plasma proteins via its surface proteins. The surface proteins studied in most detail are the M or M-like proteins, which are responsible for the ability of S. pyogenes to resist phagocytosis (1, 2).M proteins bind several human plasma proteins like fibrinogen (3), IgG (4, 5), and regulatory proteins of the complement system (6, 7). The binding activities of M proteins have been proposed to be of importance for the antiphagocytic activity of these proteins (2, 6 -9).Several different streptococcal species also bind ␣ 2 M 1 (10 -16), which is an abundant homotetrameric plasma protein of 718 kDa best characterized as a proteinase inhibitor (17). During infection proteinases are released both by bacteria and damaged host cells, and tight regulation of proteolytic activity is thus essential. S. pyogenes secretes a cysteine proteinase (SCP), which has several important functions and is regarded as a major virulence factor of this bacterium (18 -25). There is no described inhibitor of the SCP even though it is known that essentially all proteinases from the four clas...