Collagen binding is a key factor for the hemorrhagic activity of snake venom metalloproteinases |
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Authors: | Moura-da-Silva A M Ramos O H P Baldo C Niland S Hansen U Ventura J S Furlan S Butera D Della-Casa M S Tanjoni I Clissa P B Fernandes I Chudzinski-Tavassi A M Eble J A |
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Affiliation: | 1. Laboratório de Imunopatologia, Instituto Butantan, Av. Vital Brasil, 1500 - 05503-900, São Paulo, SP, Brazil;2. Laboratório de Bioquímica e Biofísica, Instituto Butantan, São Paulo, SP, Brazil;3. Institute for Physiological Chemistry, Muenster University Hospital, Muenster, Germany;4. Center for Molecular Medicine, Excellence Cluster Cardio-Pulmonary System, Frankfurt University Hospital, Frankfurt, Germany |
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Abstract: | Snake venom metalloproteinases (SVMPs) are multifunctional enzymes involved in several symptoms following snakebite, such as severe local hemorrhage. Multidomain P-III SVMPs are strongly hemorrhagic, whereas single domain P-I SVMPs are not. This indicates that disintegrin-like and cysteine-rich domains allocate motifs that enable catalytic degradation of ECM components leading to disruption of capillary vessels. Interestingly, some P-III SVMPs are completely devoid of hemorrhagic activity despite their highly conserved disintegrin-like and cysteine-rich domains. This observation was approached in the present study by comparing the effects of jararhagin, a hemorrhagic P-III SVMP, and berythractivase, a pro-coagulant and non-hemorrhagic P-III SVMP. Both toxins inhibited collagen-induced platelet aggregation, but only jararhagin was able to bind to collagen I with high affinity. The monoclonal antibody MAJar 3, that neutralizes the hemorrhagic effect of Bothrops venoms and jararhagin binding to collagen, did not react with berythractivase. The three-dimensional structures of jararhagin and berythractivase were compared to explain the differential binding to collagen and MAJar 3. Thereby, we pinpointed a motif within the Da disintegrin subdomain located opposite to the catalytic domain. Jararhagin binds to both collagen I and IV in a triple helix-dependent manner and inhibited in vitro fibrillogenesis. The jararhagin-collagen complex retained the catalytic activity of the toxin as observed by hydrolysis of fibrin. Thus, we suggest that binding of hemorrhagic SVMPs to collagens I and IV occurs through a motif located in the Da subdomain. This allows accumulation of toxin molecules at the site of injection, close to capillary vessels, where their catalytic activity leads to a local hemorrhage. Toxins devoid of this motif would be more available for vascular internalization leading to systemic pro-coagulant effects. This reveals a novel function of the disintegrin domain in hemorrhage formation. |
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Keywords: | Metalloproteinase Structure Collagen Platelets Hemorrhage Disintegrin |
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