Crystal structure of the zymogen form of the group A Streptococcus virulence factor SpeB: An integrin-binding cysteine protease

Abstract

Pathogenic bacteria secrete protein toxins that weaken or disable their host, and thereby act as virulence factors. We have determined the crystal structure of streptococcal pyrogenic exotoxin B (SpeB), a cysteine protease that is a major virulence factor of the human pathogen Streptococcus pyogenes and participates in invasive disease episodes, including necrotizing fasciitis. The structure, determined for the 40-kDa precursor form of SpeB at 1.6-A resolution, reveals that the protein is a distant homologue of the papain superfamily that includes the mammalian cathepsins B, K, L, and S. Despite negligible sequence identity, the protease portion has the canonical papain fold, albeit with major loop insertions and deletions. The catalytic site differs from most other cysteine proteases in that it lacks the Asn residue of the Cys-His-Asn triad. The prosegment has a unique fold and inactivation mechanism that involves displacement of the catalytically essential His residue by a loop inserted into the active site. The structure also reveals the surface location of an integrin-binding Arg-Gly-Asp (RGD) motif that is a feature unique to SpeB among cysteine proteases and is linked to the pathogenesis of the most invasive strains of S. pyogenes.

Insight into the molecular basis of pathogen abundance: Group AStreptococcusinhibitor of complement inhibits bacterial adherence and internalization into human cells

“…However, the molecular adaptations that specifically assist M1 strains to survive host defenses and cause widespread human disease are now being revealed. Serotype M1 strains have a naturally occurring single amino acid polymorphism in the extracellular cysteine protease virulence factor that creates a surface-exposed integrin-binding Arg-GlyAsp (RGD) motif, distinct from the Arg-Ser-Asp sequence found in other GAS organisms (30). Numerically abundant serotype M1 strains contain at least 70 kb of prophage DNA encoding the potent superantigen streptococcal pyrogenic exotoxin A (scarlet fever toxin) (2) and many other molecules.…”

Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG

“…Extracellular bacterial cysteine proteinases have also been characterized from other pathogenic bacteria such as Clostridium histolyticum, Porphyromonas gingivalis, and Staphylococcus aureus (2). These cysteine proteinases exhibit broad substrate specificity and are consequently expressed as proenzymes, requiring proteolytic processing to convert into their mature forms (7)(8)(9)(10)(11)(12)(13)(14).…”

Novel proteases: common themes and surprising features

“…Three domains, domains II-IV, form a 40 Å long groove that exhibits high specificity for the N terminus of MAPK kinases; two recent structures of mammalian zinc-metalloproteases also displayed extended peptide-binding grooves formed by helical extensions of the zinc-metalloprotease fold [31,32]. Also within the review period, Kagawa et al [33] reported the structure of SpeB precursor, a virulence factor from Streptococcus pyogenes. The structure revealed that this protein is a distant member of the papain superfamily of cysteine proteases.…”