JARARHAGIN, AN EXAMPLE OF FUNCTION VERSATILITY OF VENOM TOXINS

Ana M. Moura-da-Silva

Laboratório de Imunopatologia, Instituto Butantan, São Paulo, Brazil.

Jararhagin is a 52 kDa hemorrhagic P-III metalloproteinase isolated from the venom of Bothrops jararaca. It is a member of the reprolysin family of zinc metalloproteinases containing a catalytic metalloproteinase domain followed by a disintegrin-like and a cysteine-rich domain. The impact of jararhagin on several biological systems has been extensively studied using in vitro and in vivo model systems as well as in clinical studies. The most prominent function of jararhagin is the induction of hemorrhage as a result of the degradation of sub-endothelial matrix proteins leading to the disruption of the blood vessel endothelium. Jararhagin further compromises hemostasis through the degradation of clotting proteins such as fibrinogen and by the inhibition of platelet aggregation. Collagen-induced platelet aggregation is inhibited by jararhagin though the binding of the molecule to the 2 subunit I domain of the platelet surface 21 integrin (collagen receptor). The inhibition of platelet aggregation has been attributed to a disintegrin-like activity, selective to 21 integrin. However, functional motifs contained in all domains appear to be effective in interacting with the integrin. The versatility of jararhagin is further demonstrated by its direct action on cell systems other than platelets: in fibroblasts, jararhagin functions as a collagen-mimetic substrate and in endothelial cells, it causes apoptosis and indirectly inhibits cell proliferation by release of angiostatin-like compounds. Jararhagin induces a strong pro-inflammatory response characterized by intense leukocyte accumulation at the site of the injection. Although hemorrhage and edema are a response to the direct effect of jararhagin, jararhagin-induced inflammation is dependent on macrophages and key pro-inflammatory cytokines or their receptors. Some data also indicate that the toxin possesses anti-tumorgenic properties. Anti-jararhagin monoclonal antibodies and antibodies raised through DNA immunization have been produced and comprise important tools to understand jararhagin structure-function relationships and immunological cross-reactivity with other SVMPs. The availability of jararhagin makes it an important tool for research into the mechanisms of action of similar toxins, for insights into cellular interactions and for clinical investigations into the treatment of bites from B. jararaca.