Atroxlysin-III, A Metalloproteinase from the Venom of the Peruvian Pit Viper Snake Bothrops atrox (Jergón) Induces Glycoprotein VI Shedding and Impairs Platelet Function

Luciana S. Oliveira, Maria Inácia Estevão-Costa, Valéria G. Alvarenga, Dan E. Vivas-Ruiz, Armando Yarleque, Augusto Martins Lima, Ana Cavaco, Johannes A. Eble, Eladio F. Sanchez

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article number3489
JournalMolecules
Volume24
Issue number19
DOIs
StatePublished - 26 Sep 2019

Bibliographical note

Funding Information:
Funding: This research was funded by Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG: AUC-00022-16, CBB-APQ-01858-15, BIP-00115-18), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq: 421817/2016-0) and from Deutsche Forschungsgemeinschaft (DFG-grant: Eb177/13-1).

Funding Information:
This research was funded by Funda??o de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG: AUC-00022-16, CBB-APQ-01858-15, BIP-00115-18), Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq: 421817/2016-0) and from Deutsche Forschungsgemeinschaft (DFG-grant: Eb177/13-1). We thank Dario Souza and Silea Gontijo for their technical assistance on in vivo and chromatographic assays.

Publisher Copyright:
© 2019 by the authors.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Atroxlysin-III
  • Extracellular matrix
  • Glycoprotein VI
  • Metalloproteinase/disintegrin
  • Platelets
  • Snake venoms

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