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.
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Research Article|
January 20 2014
Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants
Simon M. Cook;
Simon M. Cook
*Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia
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Amanda Skora;
Amanda Skora
*Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia
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Mark J. Walker;
Mark J. Walker
†School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
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Martina L. Sanderson-Smith;
Martina L. Sanderson-Smith
*Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia
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Jason D. McArthur
Jason D. McArthur
1
*Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia
1To whom correspondence should be addressed (email jasonm@uow.edu.au).
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Publisher: Portland Press Ltd
Received:
October 01 2013
Revision Received:
November 22 2013
Accepted:
November 22 2013
Accepted Manuscript online:
November 22 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 458 (1): 23–31.
Article history
Received:
October 01 2013
Revision Received:
November 22 2013
Accepted:
November 22 2013
Accepted Manuscript online:
November 22 2013
Citation
Simon M. Cook, Amanda Skora, Mark J. Walker, Martina L. Sanderson-Smith, Jason D. McArthur; Site-restricted plasminogen activation mediated by group A streptococcal streptokinase variants. Biochem J 15 February 2014; 458 (1): 23–31. doi: https://doi.org/10.1042/BJ20131305
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