@article{ref1,
title="Collagen binding is a key factor for the hemorrhagic activity of snake venom metalloproteinases",
journal="Biochimie",
year="2008",
author="Moura-da-Silva, A. M. and Ramos, O. H. P. and Baldo, C. and Niland, S. and Hansen, U. and Ventura, J. S. and Furlan, S. and Butera, D. and Della-Casa, M. S. and Tanjoni, I. and Clissa, P. B. and Fernandes, I. and Chudzinski-Tavassi, A. M. and Eble, J. A.",
volume="90",
number="3",
pages="484-492",
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.<p /><p>Language: en</p>",
language="en",
issn="0300-9084",
doi="10.1016/j.biochi.2007.11.009",
url="http://dx.doi.org/10.1016/j.biochi.2007.11.009"
}