title: Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants.
abstract: SK (streptokinase) is a secreted plasminogen activator and virulence factor of GAS (group A Streptococcus). Among GAS isolates, SK gene sequences are polymorphic and are grouped into two sequence clusters (cluster type-1 and cluster type-2) with cluster type-2 being further classified into subclusters (type-2a and type-2b). In the present study, we examined the role of bacterial and host-derived cofactors in SK-mediated plasminogen activation. All SK variants, apart from type-2b, can form an activator complex with Glu-Plg (Glu-plasminogen). Specific ligand-binding-induced conformational changes in Glu-Plg mediated by fibrinogen, PAM (plasminogen-binding group A streptococcal M protein), fibrinogen fragment D or fibrin, were required for type-2b SK to form a functional activator complex with Glu-Plg. In contrast with type-1 and type-2a SK, type-2b SK activator complexes were inhibited by α2-antiplasmin unless bound to fibrin or to the GAS cell-surface via PAM in combination with fibrinogen. Taken together, these data suggest that type-2b SK plasminogen activation may be restricted to specific microenvironments within the host such as fibrin deposits or the bacterial cell surface through the action of α2-antiplasmin. We conclude that phenotypic SK variation functionally underpins a pathogenic mechanism whereby SK variants differentially focus plasminogen activation, leading to specific niche adaption within the host.
authors.affiliation: *Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Cook
authors.affiliation: *Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Skora
authors.affiliation: †School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: *Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Martina L
authors.initials: ML
authors.lastname: Sanderson-Smith
authors.affiliation: *Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Jason D
authors.initials: JD
authors.lastname: McArthur
mesh_terms: D020134:Catalytic Domain; D010958:Plasminogen / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000201:enzymology*; D013300:Streptokinase / Q000378:metabolism*
chemical_list: D010958:Plasminogen; D013300:Streptokinase