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

0490992 - BC 2019 RIV GB eng J - Článek v odborném periodiku
Assumpção, T.C. - Mizurini, D.M. - Ma, D. - Monteiro, R.Q. - Ahlstedt, S. - Reyes, M. - Kotsyfakis, Michalis - Mather, T. N. - Andersen, J. F. - Lukszo, J. - Ribeiro, J.M.C. - Francischetti, I.M.B.
Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis.
Scientific Reports. Roč. 8, 19 March (2018), č. článku 4806. ISSN 2045-2322. E-ISSN 2045-2322
Grant CEP: GA ČR GAP502/12/2409
Institucionální podpora: RVO:60077344
Klíčová slova: factor pathway inhibitor * heparin-binding exosite * ixodes-scapularis * borrelia-burgdorferi * factor-xa * hematophagous animals * platelet-aggregation * potent inhibitor
Obor OECD: Genetics and heredity (medical genetics to be 3)
Impakt faktor: 4.011, rok: 2018
https://www.nature.com/articles/s41598-018-22780-1

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 e-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 (K-D 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.
Trvalý link: http://hdl.handle.net/11104/0285092