Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis
2018
Tick saliva is a rich source of modulators of vascular biology. We have characterized Ixonnexin, a member of the “Basic-tail” family of salivary proteins from the tick
Ixodes scapularis. Ixonnexin is a 104 residues (11.8 KDa), non-enzymatic basic protein which contains 3 disulfide bonds and a C-terminal rich in lysine. It is homologous to SALP14, a tick salivary FXa anticoagulant. Ixonnexin was produced by ligation of synthesized fragments (51–104) and (1–50) followed by folding. Ixonnexin, like SALP14, interacts with FXa. Notably, Ixonnexin also modulates
fibrinolysisin vitro by a unique salivary mechanism. Accordingly, it accelerates
plasminogen activationby tissue-type
plasminogen activator(t-PA) with Km 100 nM; however, it does not affect
urokinase-mediated
fibrinolysis. Additionally, lysine analogue e-
aminocaproic acidinhibits Ixonnexin-mediated
plasmingeneration implying that lysine-binding sites of
Kringle domain(s) of plasminogen or t-PA are involved in this process. Moreover, surface plasmon resonance experiments shows that Ixonnexin binds t-PA, and plasminogen (KD 10 nM), but not
urokinase. These results imply that Ixonnexin promotes
fibrinolysisby supporting the interaction of plasminogen with t-PA through formation of an enzymatically productive
ternary complex. Finally, in vivo experiments demonstrates that Ixonnexin inhibits FeCl3-induced thrombosis in mice. Ixonnexin emerges as novel modulator of
fibrinolysiswhich may also affect parasite-vector-host interactions.
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