Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis.

Abstract

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 fibrinolysis in vitro by a unique salivary mechanism. Accordingly, it accelerates plasminogen activation by tissue-type plasminogen activator (t-PA) with Km 100 nM; however, it does not affect urokinase-mediated fibrinolysis. Additionally, lysine analogue ε-aminocaproic acid inhibits Ixonnexin-mediated plasmin generation 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 fibrinolysis by 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 fibrinolysis which may also affect parasite-vector-host interactions.

• Authors: Teresa C Assumpção, Daniella M Mizurini, Dongying Ma, Robson Q Monteiro, Sydney Ahlstedt, Morayma Reyes, Michail Kotsyfakis, Thomas N Mather, John F Andersen, Jan Lukszo, José M C Ribeiro, Ivo M B Francischetti
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 4806 (03 19 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29555911 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chlorides
• Ferric Compounds
• Noxae
• Salivary Proteins and Peptides
• Plasminogen
• Tissue Plasminogen Activator
• ferric chloride

Topics

• Animals
• Arterial Occlusive Diseases (chemically induced, pathology, prevention & control)
• Chlorides (toxicity)
• Ferric Compounds (toxicity)
• Fibrinolysis (drug effects)
• Mice
• Noxae (toxicity)
• Plasminogen (metabolism)
• Saliva (metabolism)
• Salivary Proteins and Peptides (pharmacology)
• Thrombosis (chemically induced, pathology, prevention & control)
• Ticks (metabolism)
• Tissue Plasminogen Activator (metabolism)