title: Variable region in streptococcal M-proteins provides stable binding with host fibrinogen for plasminogen-mediated bacterial invasion.
abstract: Dimeric M-proteins (M-Prt) in group AStreptococcus pyogenes(GAS) are surface-expressed virulence factors implicated in processes that contribute to the pathogenicity of infection. Sequence analyses of various GAS M-Prts have shown that they contain a highly conserved sortase A-dependent cell wall-anchored C terminus, whereas the surface-exposed N terminus is highly variable, a feature used for identification and serotyping of various GAS strains. This variability also allows for strain-specific responses that suppress host defenses. Previous studies have indeed identified the N-terminal M-Prt B-domain as the site interacting with antiphagocytotic human-host fibrinogen (hFg). Herein, we show that hFg strongly interacts with M-Prts containing highly variable B-domains. We further demonstrate that specific GAS clinical isolates display high affinity for the D-domain of hFg, and this interaction allowed for subsequent surface binding of human-host plasminogen (hPg) to the E-domain of hFg. This GAS surface-bound hPg is then activated by GAS-secreted streptokinase, leading to the generation of an invasive proteolytic bacterial surface. Our results underscore the importance of the human fibrinolytic system in host-pathogen interactions in invasive GAS infections.
authors.affiliation: From the W.M. Keck Center for Transgene Research and.|the Departments of Chemistry and Biochemistry and.
authors.forename: Kristofor
authors.initials: K
authors.lastname: Glinton
authors.affiliation: From the W.M. Keck Center for Transgene Research and.|the Departments of Chemistry and Biochemistry and.
authors.forename: Julia
authors.initials: J
authors.lastname: Beck
authors.affiliation: From the W.M. Keck Center for Transgene Research and.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liang
authors.affiliation: From the W.M. Keck Center for Transgene Research and.|the Departments of Chemistry and Biochemistry and.
authors.forename: Cunjia
authors.initials: C
authors.lastname: Qiu
authors.affiliation: From the W.M. Keck Center for Transgene Research and.|Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556.
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: From the W.M. Keck Center for Transgene Research and.|the Departments of Chemistry and Biochemistry and.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.affiliation: From the W.M. Keck Center for Transgene Research and fcastell@nd.edu.|the Departments of Chemistry and Biochemistry and.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry*; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D002473:Cell Wall / Q000737:chemistry; D004330:Drosophila; D004926:Escherichia coli / Q000737:chemistry; D005340:Fibrinogen / Q000737:chemistry*; D005342:Fibrinolysis; D054884:Host-Pathogen Interactions; D006801:Humans; D010802:Phylogeny; D010958:Plasminogen / Q000737:chemistry*; D011485:Protein Binding; D000072417:Protein Domains; D011994:Recombinant Proteins / Q000737:chemistry; D013297:Streptococcus pyogenes / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D011994:Recombinant Proteins; C014689:streptococcal M protein; D005340:Fibrinogen; D010958:Plasminogen
keywords: M-protein; bacterial pathogenesis; biophysics; cell surface protein; fibrinogen; fibrinolysis