Dataset Information

The ?-domain of streptokinase affects several functionalities, including specific/proteolytic activity kinetics.

ABSTRACT: Streptokinase (SK) is a plasminogen activator which converts inactive plasminogen (Pg) to active plasmin (Pm), which cleaves fibrin clots. SK secreted by groups A, C, and G Streptococcus (SKA/SKC/SKG) is composed of three domains: SK?, SK? and SK?. Previous domain-swapping studies between SK1/SK2b-cluster variants revealed that SK? plays a major role in the activation of human Pg. Here, we carried out domain-swapping between skcg-SK/SK2-cluster variants to determine the involvement of SK? in several SK functionalities, including specific/proteolytic activity kinetics, fibrinogen-bound Pg activation and ?2 -antiplasmin resistance. Our results indicate that SK? has a minor to determining role in these diverse functionalities for skcg-SK and SK2b variants, which might potentially be accompanied by few critical residues acting as hot spots. Our findings enhance our understanding of the roles of SK? and hot spots in different functional characteristics of SK clusters and may aid in the engineering of fibrin-specific variants of SK for breaking down blood clots with potentially higher efficacy and safety.

SUBMITTER: Rafipour M

PROVIDER: S-EPMC6609762 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The β-domain of streptokinase affects several functionalities, including specific/proteolytic activity kinetics.

Rafipour Maryam M Keramati Malihe M Aslani Mohammad Mehdi MM Arashkia Arash A Roohvand Farzin F

FEBS open bio 20190530 7

Streptokinase (SK) is a plasminogen activator which converts inactive plasminogen (Pg) to active plasmin (Pm), which cleaves fibrin clots. SK secreted by groups A, C, and G Streptococcus (SKA/SKC/SKG) is composed of three domains: SKα, SKβ and SKγ. Previous domain-swapping studies between SK1/SK2b-cluster variants revealed that SKβ plays a major role in the activation of human Pg. Here, we carried out domain-swapping between skcg-SK/SK2-cluster variants to determine the involvement of SKβ in sev ...[more]

PMID: 31087538

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Project description:Enzymes are catalysts in biochemical reactions that, by definition, increase rates of reactions without being altered or destroyed. However, when that enzyme is a protease, a subclass of enzymes that hydrolyze other proteins, and that protease is in a multiprotease system, protease-as-substrate dynamics must be included, challenging assumptions of enzyme inertness, shifting kinetic predictions of that system. Protease-on-protease inactivating hydrolysis can alter predicted protease concentrations used to determine pharmaceutical dosing strategies. Cysteine cathepsins are proteases capable of cathepsin cannibalism, where one cathepsin hydrolyzes another with substrate present, and misunderstanding of these dynamics may cause miscalculations of multiple proteases working in one proteolytic network of interactions occurring in a defined compartment. Once rates for individual protease-on-protease binding and catalysis are determined, proteolytic network dynamics can be explored using computational models of cooperative/competitive degradation by multiple proteases in one system, while simultaneously incorporating substrate cleavage. During parameter optimization, it was revealed that additional distraction reactions, where inactivated proteases become competitive inhibitors to remaining, active proteases, occurred, introducing another network reaction node. Taken together, improved predictions of substrate degradation in a multiple protease network were achieved after including reaction terms of autodigestion, inactivation, cannibalism, and distraction, altering kinetic considerations from other enzymatic systems, since enzyme can be lost to proteolytic degradation. We compiled and encoded these dynamics into an online platform (https://plattlab.shinyapps.io/catKLS/) for individual users to test hypotheses of specific perturbations to multiple cathepsins, substrates, and inhibitors, and predict shifts in proteolytic network reactions and system dynamics.

Dataset Information

The ?-domain of streptokinase affects several functionalities, including specific/proteolytic activity kinetics.

Publications

The β-domain of streptokinase affects several functionalities, including specific/proteolytic activity kinetics.

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