Please use this identifier to cite or link to this item: https://doi.org/10.1096/fj.201601216R
Title: Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, Amblyomma variegatum
Authors: Iyer, Janaki Krishnamoorthy
Koh, Cho Yeow 
Kazimirova, Maria
Roller, Ladislav
Jobichen, Chacko
Swaminathan, Kunchithapadam 
Mizuguchi, Jun
Iwanaga, Sadaaki
Nuttall, Patricia A
Chan, Mark Y 
Kini, R Manjunatha 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biology
Cell Biology
Life Sciences & Biomedicine - Other Topics
direct thrombin inhibitor
exosite-I inhibitor
blood-feeding arthropods
blood-sucking animals
thrombin-inhibitor complex
BRADYKININ-POTENTIATING PEPTIDES
TROPICAL BONT TICK
ORAL ANTICOAGULANTS
HEPARIN
IDENTIFICATION
BIVALIRUDIN
COMPLEXES
HIRUDIN
PROTEIN
VENOM
Issue Date: 1-Jul-2017
Publisher: FEDERATION AMER SOC EXP BIOL
Citation: Iyer, Janaki Krishnamoorthy, Koh, Cho Yeow, Kazimirova, Maria, Roller, Ladislav, Jobichen, Chacko, Swaminathan, Kunchithapadam, Mizuguchi, Jun, Iwanaga, Sadaaki, Nuttall, Patricia A, Chan, Mark Y, Kini, R Manjunatha (2017-07-01). Avathrin: a novel thrombin inhibitor derived from a multicopy precursor in the salivary glands of the ixodid tick, Amblyomma variegatum. FASEB JOURNAL 31 (7) : 2981-2995. ScholarBank@NUS Repository. https://doi.org/10.1096/fj.201601216R
Abstract: Tick saliva is a rich source of antihemostatic compounds.We amplified a cDNAfrom the salivary glands of the tropical bont tick (Amblyomma variegatum) using primers based on the variegin sequence, which we previously identified as a novel thrombin inhibitor from the same tick species. The transcript encodes a precursor protein comprising a signal peptide and 5 repeats of variegin-like sequences that could be processed into multiple short peptides. These peptides share 31 to 34% identity with variegin. Here, we structurally and functionally characterized one of these peptides named "avathrin." Avathrinis a fast, tight binding competitive inhibitorwith an affinity of 545 pM for thrombin and is 4 orders of magnitude more selective towards thrombin than to the other serine proteases of the coagulation cascade. The crystal structure of thrombin-avathrin complex at 2.09 Å revealed that avathrin interacts with the thrombin active site and exosite-I. Although avathrin is cleaved by thrombin, the C-terminal cleavage product continues to exert prolonged inhibition. Avathrin is more potent than hirulog-1 in a murine carotid artery thrombosis model. Such precursor proteins that could be processed into multiple thrombin inhibiting peptides appear to be widespread among Amblyomminae, providing an enormous library of molecules for development as potent antithrombotics.
Source Title: FASEB JOURNAL
URI: https://scholarbank.nus.edu.sg/handle/10635/206156
ISSN: 08926638
15306860
DOI: 10.1096/fj.201601216R
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