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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Panizzi, Peter Fuentes-prior, Pablo Thompson, Michael W. Laha, Malabika Tharp, Anthony C. Bock, Paul E. |
| Description | Author Affiliation: Tharp AC ( Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.) |
| Abstract | Streptokinase (SK) conformationally activates the central zymogen of the fibrinolytic system, plasminogen (Pg). The SK.Pg* catalytic complex binds Pg as a specific substrate and cleaves it into plasmin (Pm), which binds SK to form the SK.Pm complex that propagates Pm generation. Catalytic complex formation is dependent on lysine-binding site (LBS) interactions between a Pg/Pm kringle and the SK COOH-terminal Lys(414). Pg substrate recognition is also LBS-dependent, but the kringle and SK structural element(s) responsible have not been identified. SK mutants lacking Lys(414) with Ala substitutions of charged residues in the SK beta-domain 250-loop were evaluated in kinetic studies that resolved conformational and proteolytic Pg activation. Activation of [Lys]Pg and mini-Pg (containing only kringle 5 of Pg) by SK with Ala substitutions of Arg(253), Lys(256), and Lys(257) showed decreases in the bimolecular rate constant for Pm generation, with nearly total inhibition for the SK Lys(256)/Lys(257) double mutant. Binding of bovine Pg (BPg) to the SK.Pm complex containing fluorescently labeled Pm demonstrated LBS-dependent assembly of a SK.labeled Pm.BPg ternary complex, whereas BPg did not bind to the complex containing the SK Lys(256)/Lys(257) mutant. BPg was activated by SK.Pm with a K(m) indistinguishable from the K(D) for BPg binding to form the ternary complex, whereas the SK Lys(256)/Lys(257) mutant did not support BPg activation. We conclude that SK residues Arg(253), Lys(256), and Lys(257) mediate Pg substrate recognition through kringle 5 of the [Lys]Pg and mini-Pg substrates. A molecular model of the SK.kringle 5 complex identifies the putative interactions involved in LBS-dependent Pg substrate recognition. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 29 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-07-17 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Kringles Plasminogen Metabolism Protein Structure, Tertiary Streptokinase Algorithms Animals Arginine Chemistry Genetics Binding Sites Catalysis Drug Combinations Kinetics Lysine Models, Molecular Mutation Protein Conformation Substrate Specificity Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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