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Structural diversity of streptokinase and activation of human plasminogen.

ABSTRACT: The beta domain of streptokinase is required for plasminogen activation and contains a region of sequence diversity associated with infection and disease in group A streptococci. We report that mutagenesis of this polymorphic region does not alter plasminogen activation, which suggests an alternative function for this molecular motif in streptococcal disease.

SUBMITTER: Lizano S

PROVIDER: S-EPMC1168554 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

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Structural diversity of streptokinase and activation of human plasminogen.

Lizano Sergio S Johnston Kenneth H KH

Infection and immunity 20050701 7

The beta domain of streptokinase is required for plasminogen activation and contains a region of sequence diversity associated with infection and disease in group A streptococci. We report that mutagenesis of this polymorphic region does not alter plasminogen activation, which suggests an alternative function for this molecular motif in streptococcal disease. ...[more]

PMID: 15972548

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Function of streptokinase fragments in plasminogen activation.

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Streptococcus co-opts a conformational lock in human plasminogen to facilitate streptokinase cleavage and bacterial virulence.

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Plasminogen substrate recognition by the streptokinase-plasminogen catalytic complex is facilitated by Arg253, Lys256, and Lys257 in the streptokinase beta-domain and kringle 5 of the substrate.

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Kinetic studies on the interaction of streptokinase and other plasminogen activators with plasminogen and fibrin.

Project description:The activation of Lys-plasminogen to plasmin by streptokinase was promoted by soluble fibrin such that Km was decreased and Vmax. increased. Enhancement was also observed when Glu-plasminogen was the substrate and was shared by the preformed streptokinase-plasminogen activator complex, indicating that the stimulation was not exerted primarily on the rate of active site formation.

| S-EPMC1145091 | biostudies-other

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| S-EPMC6900475 | biostudies-literature

Ligand binding modulates the structural dynamics and activity of urokinase-type plasminogen activator: A possible mechanism of plasminogen activation.

Project description:The catalytic activity of trypsin-like serine proteases is in many cases regulated by conformational changes initiated by binding of physiological modulators to exosites located distantly from the active site. A trypsin-like serine protease of particular interest is urokinase-type plasminogen activator (uPA), which is involved in extracellular tissue remodeling processes. Herein, we used hydrogen/deuterium exchange mass spectrometry (HDXMS) to study regulation of activity in the catalytic domain of the murine version of uPA (muPA) by two muPA specific monoclonal antibodies. Using a truncated muPA variant (muPA16-243), containing the catalytic domain only, we show that the two monoclonal antibodies, despite binding to an overlapping epitope in the 37s and 70s loops of muPA16-243, stabilize distinct muPA16-243 conformations. Whereas the inhibitory antibody, mU1 was found to increase the conformational flexibility of muPA16-243, the stimulatory antibody, mU3, decreased muPA16-243 conformational flexibility. Furthermore, the HDXMS data unveil the existence of a pathway connecting the 70s loop to the active site region. Using alanine scanning mutagenesis, we further identify the 70s loop as an important exosite for the activation of the physiological uPA substrate plasminogen. Thus, the data presented here reveal important information about dynamics in uPA by demonstrating how various ligands can modulate uPA activity by mediating long-range conformational changes. Moreover, the results provide a possible mechanism of plasminogen activation.

| S-EPMC5805342 | biostudies-literature

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