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Abstract

Streptokinase (SK) from Group A streptococcus (GAS) activates human plasminogen to generate plasmin, which degrades fibrin clots tofacilitate bacterial dissemination. Sequence variants of SK from diverse GAS strains form distinct evolutionary clusters.Unlike cluster 1 SK, cluster 2 variants have very little activity in solution and depend on co-factors (e.g. fibrin(ogen)).Cluster 2 SK variants also appear to correlate with cell-surface M-like proteins: SK2a with M1 (fibrinogen-binding) and SK2b with PAM (plasminogen-binding).

Plasminogen activation by recombinant SKs (rSK2a, rSK2b) was investigated by chromogenic assay; nickel-coated microtiter plates were used to immobilise recombinant M proteins (rPAM and rM1) via a C–terminal His tag to mimic cell surface plasmin generation.

Plasminogen activation by rSK2b is stimulated ∼18-fold by rPAM in solution; when rPAM is immobilised stimulation exceeds 100-fold. Fibrin is the most potent stimulator of rSK2a activity (7-fold increase) compared to fibrinogen (4-fold); when rM1 was included, either in solution or immobilised, there was no further stimulation of rSK2a activity with fibrinogen.

Stimulation ofSK2b activity by plasminogen bound to immobilised PAM suggests an important role for cell-surface plasmin generation. SK2a activity appears to be independent of M1, targeting fibrin directly. SK variants are commonly associated with distinct disease manifestations with SK2b commonly expressed by invasive skin-tropic strains of GAS and SK2a by nasopharynx-tropic strains. An improved understanding of the molecular mechanism of action by GAS SK variants may help to identify potential novel therapeutic targets for the treatment of invasive GAS diseases.

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/content/journal/acmi/10.1099/acmi.ac2020.po0860
2020-07-10
2021-02-26
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http://instance.metastore.ingenta.com/content/journal/acmi/10.1099/acmi.ac2020.po0860
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