Binding of the COOH-terminal Lysine Residue of Streptokinase to Plasmin(ogen) Kringles Enhances Formation of the Streptokinase{middle dot}Plasmin(ogen) Catalytic Complexes.
Streptokinase (SK) activates human fibrinolysis by inducing non-proteolytic activation of the serine proteinase zymogen, plasminogen ( Pg), in the SK.Pg* catalytic complex. SK.Pg* proteolytically activates Pg to plasmin (Pm). SK-induced Pg activation is enhanced by lysine-binding site (LBS) interactions with kringles on Pg and Pm, as evidenced by inhibition of the reactions by the lysine analogue, 6-aminohexanoic acid. Equilibrium binding analysis and [Lys]Pg activation kinetics with wild-type SK, carboxypeptidase B-treated SK, and a COOH-terminal Lys(414) deletion mutant (SKDeltaK414) demonstrated a critical role for Lys(414) in the enhancement of [Lys]Pg and [Lys]Pm binding and conformational [Lys]Pg activation. The LBS-independent affinity of SK for [Glu]Pg was unaffected by deletion of Lys(414). By contrast, removal of SK Lys(414) caused 19- and 14-fold decreases in SK affinity for [Lys]Pg and [Lys]Pm binding in the catalytic mode, respectively. In kinetic studies of the coupled conformational and proteolytic activation of [Lys]Pg, SKDeltaK414 exhibited a corresponding 17-fold affinity decrease for formation of the SKDeltaK414.[Lys]Pg* complex. SKDeltaK414 binding to [Lys]Pg and [Lys]Pm and conformational [Lys]Pg activation were LBS-independent, whereas [Lys]Pg substrate binding and proteolytic [Lys]Pm generation remained LBS-dependent. We conclude that binding of SK Lys(414) to [Lys]Pg and [Lys]Pm kringles enhances SK.[Lys]Pg* and SK.[Lys]Pm catalytic complex formation. This interaction is distinct structurally and functionally from LBS-dependent Pg substrate recognition by these complexes.[1]References
- Binding of the COOH-terminal Lysine Residue of Streptokinase to Plasmin(ogen) Kringles Enhances Formation of the Streptokinase{middle dot}Plasmin(ogen) Catalytic Complexes. Panizzi, P., Boxrud, P.D., Verhamme, I.M., Bock, P.E. J. Biol. Chem. (2006) [Pubmed]
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