title: 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.
authors.affiliation: School of Biological Sciences, Department of Chemistry, University of Auckland, Private Bag 92-019, Auckland, New Zealand.
authors.forename: T F
authors.initials: TF
authors.lastname: Kagawa
authors.forename: J C
authors.initials: JC
authors.lastname: Cooney
authors.forename: H M
authors.initials: HM
authors.lastname: Baker
authors.forename: S
authors.initials: S
authors.lastname: McSweeney
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Gubba
authors.forename: J M
authors.initials: JM
authors.lastname: Musser
authors.forename: E N
authors.initials: EN
authors.lastname: Baker
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D004792:Enzyme Precursors / Q000737:chemistry* / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D013297:Streptococcus pyogenes / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D004792:Enzyme Precursors; D016023:Integrins; D003546:Cysteine Endopeptidases; C042477:streptopain