Abstract
Atroxlysin-III (Atr-III) was purified from the venom of Bothrops atrox. This 56-kDa protein bears N-linked glycoconjugates and is a P-III hemorrhagic metalloproteinase. Its cDNA-deduced amino acid sequence reveals a multidomain structure including a proprotein, a metalloproteinase, a disintegrin-like and a cysteine-rich domain. Its identity with bothropasin and jararhagin from Bothrops jararaca is 97% and 95%, respectively. Its enzymatic activity is metal ion-dependent. The divalent cations, Mg2+ and Ca2+, enhance its activity, whereas excess Zn2+ inhibits it. Chemical modification of the Zn2+-complexing histidine residues within the active site by using diethylpyrocarbonate (DEPC) inactivates it. Atr-III degrades plasma fibronectin, type I-collagen, and mainly the α-chains of fibrinogen and fibrin. The von Willebrand factor (vWF) A1-domain, which harbors the binding site for GPIb, is not hydrolyzed. Platelets interact with collagen via receptors for collagen, glycoprotein VI (GPVI), and α2β1 integrin. Neither the α2β1 integrin nor its collagen-binding A-domain is fragmented by Atr-III. In contrast, Atr-III cleaves glycoprotein VI (GPVI) into a soluble ~55-kDa fragment (sGPVI). Thereby, it inhibits aggregation of platelets which had been stimulated by convulxin, a GPVI agonist. Selectively, Atr-III targets GPVI antagonistically and thus contributes to the antithrombotic effect of envenomation by Bothrops atrox.
Highlights
Bioactive snake venom compounds have evolved from convergent or divergent evolution [1,2,3].Due to their high efficacy, several venom proteins/peptides, which interfere with hemostasis by affecting coagulation and/or platelet function, have been harnessed in the diagnosis and treatment of hemostatic disorders [4,5,6,7]
Our results of its biochemical and functional properties reveal the molecular mechanism of Atr-III on platelet function, hemostasis, and thrombosis
The D-domain contains a putative integrin-interacting motif ECD in the corresponding D-domain sequence that is homologous to DCD, a putative collagen binding site, which is characteristic for many P-III Snake venom metalloproteinases (SVMPs)
Summary
Bioactive snake venom compounds have evolved from convergent or divergent evolution [1,2,3]. P-IV), containing an additional snake C-type lectin-like proteins (snaclecs) [10,11,12,13,14,15], has been included in the P-III class as a subclass (P-IIId) since no mRNA transcript has been found until now The criterion for this classification was based on the presence or absence of several non-catalytic domains as evidenced via mRNA transcripts and proteins purified in the venom [11]. The most clinical manifestations of B. atrox bite are local tissue damage and/or severe systemic hemorrhages, and may vary in different regions of the Amazonian range [25,26,27] These detrimental effects are induced mostly by SVMPs such as the P-I class toxin termed atroxlysin-I (Atr-I) previously characterized in our laboratory [13]. Our results of its biochemical and functional properties reveal the molecular mechanism of Atr-III on platelet function, hemostasis, and thrombosis
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