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Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin

SYSNO ASEP	0451374
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin
Author(s)	Jablonka, W. (US) Kotsyfakis, Michalis (BC-A)_{RID, ORCID} Mizurini, D.M. (BR) Monteiro, R.Q. (BR) Lukszo, J. (US) Drake, S.K. (US) Ribeiro, J.M.C. (US) Andersen, J. F. (US)
Source Title	PLoS ONE. - : Public Library of Science - ISSN 1932-6203 Roč. 10, č. 8 (2015), e0133991
Number of pages	16 s.
Publication form	Online - E
Language	eng - English
Country	US - United States
Keywords	Haemaphysalis longicornis ; binding inhibitor ; crystal structure
Subject RIV	EB - Genetics ; Molecular Biology
R&D Projects	GAP502/12/2409 GA ČR - Czech Science Foundation (CSF)
Institutional support	BC-A - RVO:60077344
UT WOS	000359061400061
DOI	10.1371/journal.pone.0133991
Annotation	A group of peptides from the salivary gland of the tick Hyalomma marginatum rufipes, a vector of Crimean Congo hemorrhagic fever show weak similarity to the madanins, a group of thrombin-inhibitory peptides from a second tick species, Haemaphysalis longicornis. We have evaluated the anti-serine protease activity of one of these H. marginatum peptides that has been given the name hyalomin-1. Hyalomin-1 was found to be a selective inhibitor of thrombin, blocking coagulation of plasma and inhibiting S2238 hydrolysis in a competitive manner with an inhibition constant (Ki) of 12 nM at an ionic strength of 150 mM. It also blocks the thrombin-mediated activation of coagulation factor XI, thrombin-mediated platelet aggregation, and the activation of coagulation factor V by thrombin. Hyalomin-1 is cleaved at a canonical thrombin cleavage site but the cleaved products do not inhibit coagulation. However, the C-terminal cleavage product showed non-competitive inhibition of S2238 hydrolysis. A peptide combining the N-terminal parts of the molecule with the cleavage region did not interact strongly with thrombin, but a 24-residue fragment containing the cleavage region and the C-terminal fragment inhibited the enzyme in a competitive manner and also inhibited coagulation of plasma. These results suggest that the peptide acts by binding to the active site as well as exosite I or the autolysis loop of thrombin. Injection of 2.5 mg/kg of hyalomin-1 increased arterial occlusion time in a mouse model of thrombosis, suggesting this peptide could be a candidate for clinical use as an antithrombotic.
Workplace	Biology Centre (since 2006)
Contact	Dana Hypšová, eje@eje.cz, Tel.: 387 775 214
Year of Publishing	2016

Number of the records: 1