title: Streptococcus uberis plasminogen activator (SUPA) activates human plasminogen through novel species-specific and fibrin-targeted mechanisms.
abstract: Bacterial plasminogen (Pg) activators generate plasmin to degrade fibrin blood clots and other proteins that modulate the pathogenesis of infection, yet despite strong homology between mammalian Pgs, the activity of bacterial Pg activators is thought to be restricted to the Pg of their host mammalian species. Thus, we found that Streptococcus uberis Pg activator (SUPA), isolated from a Streptococcus species that infects cows but not humans, robustly activated bovine but not human Pg in purified systems and in plasma. Consistent with this, SUPA formed a higher avidity complex (118-fold) with bovine Pg than with human Pg and non-proteolytically activated bovine but not human Pg. Surprisingly, however, the presence of human fibrin overrides the species-restricted action of SUPA. First, human fibrin enhanced the binding avidity of SUPA for human Pg by 4-8-fold in the presence and absence of chloride ion (a negative regulator). Second, although SUPA did not protect plasmin from inactivation by α(2)-antiplasmin, fibrin did protect human plasmin, which formed a 31-fold higher avidity complex with SUPA than Pg. Third, fibrin significantly enhanced Pg activation by reducing the K(m) (4-fold) and improving the catalytic efficiency of the SUPA complex (6-fold). Taken together, these data suggest that indirect molecular interactions may override the species-restricted activity of bacterial Pg activators; this may affect the pathogenesis of infections or may be exploited to facilitate the design of new blood clot-dissolving drugs.
authors.affiliation: Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Inna P
authors.initials: IP
authors.lastname: Gladysheva
authors.forename: Aiilyan K
authors.initials: AK
authors.lastname: Houng
authors.forename: Guy L
authors.initials: GL
authors.lastname: Reed
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D002417:Cattle; D002418:Cattle Diseases / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry* / Q000378:metabolism; D005337:Fibrin / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010958:Plasminogen / Q000737:chemistry* / Q000378:metabolism; D010960:Plasminogen Activators / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013045:Species Specificity; D013291:Streptococcus / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D020536:Enzyme Activators; D005337:Fibrin; D010958:Plasminogen; D010960:Plasminogen Activators