Oxiagin from the Naja oxiana cobra venom is the first reprolysin inhibiting the classical pathway of complement

Shoibonov, B. B.; Osipov, Alexey V.; Kryukova, Elena V.; Zinchenko, Anatoly; Lakhtin, V. M.; Tsetlin, Victor I.; Utkin, Yuri N.

doi:10.1016/j.molimm.2004.11.009

Cited by 27 publications

(7 citation statements)

References 24 publications

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“…One can envision situations where the disintegrin-like/cysteine-rich domains have been proteolytically processed from the full-length PIII, and the disintegrin-like domain may support protein-protein interactions, but based on the structure, this is not likely the case in the full-length protein with the disintegrinlike/cysteine-rich domains presented in the context of the metalloproteinase domain. Interestingly in another recent study it was shown that oxiagin, a PIII metalloproteinase isolated from the venom of Naja oxiana, was able to inhibit the classical pathway of the complement system by preventing the interaction of component C2 (without its inactivation) with immobilized component C4b (40). Complement factor C2 contains a VWA domain; hence one can speculate that oxiagin interacts with C2 VWA domain via its cysteine-rich domain thus preventing the binding of C2 and C4b that is known to be dependent on Mg 2ϩ -binding sites within the VWA domain.…”

Section: Discussionmentioning

confidence: 99%

The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

Serrano

Kim

Wang

et al. 2006

Journal of Biological Chemistry

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Snake venom metalloproteinases (SVMPs) are members of the Reprolysin family of metalloproteinases to which the ADAM (a disintegrin and metalloproteinase) proteins also belong. The disintegrin-like/cysteine-rich domains of the ADAMs have been implicated in their function. In the case of the SVMPs, we hypothesized that these domains could function to target the metalloproteinases to key extracellular matrix proteins or cell surface proteins. Initially we detected interaction of collagen XIV, a fibril-associated collagen with interrupted triple helices containing von Willebrand factor A (VWA) domains, with the PIII SVMP catrocollastatin. Next we investigated whether other VWA domain-containing matrix proteins could support the binding of PIII SVMPs. Using surface plasmon resonance, the PIII SVMP jararhagin and a recombinant cysteine-rich domain from a PIII SVMP were demonstrated to bind to collagen XIV, collagen XII, and matrilins 1, 3, and 4. Jararhagin was shown to cleave these proteins predominantly at sites localized at or near the VWA domains suggesting that it is the VWA domains to which the PIII SVMPs are binding via their cysteine-rich domain. In light of the fact that these extracellular matrix proteins function to stabilize matrix, targeting the SVMPs to these proteins followed by their specific cleavage could promote the destabilization of extracellular matrix and cell-matrix interactions and in the case of capillaries could contribute to their disruption and hemorrhage. Although there is only limited structural homology shared by the cysteine-rich domains of the PIII SVMPs and the ADAMs our results suggest an analogous function for the cysteine-rich domains in certain members of the expanded ADAM family of proteins to target them to VWA domain-containing proteins.One of the hallmarks of viperid envenoming is local hemorrhage caused by the snake venom metalloproteinases (SVMPs) 2 (1, 2). SVMPs are members of the Reprolysin subfamily of the M12 family of metalloproteinases (3). Of the SVMPs, the PIII class is distinguished by being comprised of proproteinase, proteinase, disintegrin-like, and cysteine-rich domains (4). The proteinase domain of all the SVMP hemorrhagic toxins is believed to function to degrade capillary basement membranes, endothelial cell surfaces, and stromal matrix ultimately causing extravasation of capillary contents into the surround stroma (5, 6). Interestingly the PIII class of SVMPs is typically much more potent in causing hemorrhage compared with the PI and PII classes that lack the cysteine-rich domain found in the PIII class (4) suggesting a role for this domain in the pathophysiology of the PIII hemorrhagic toxins. Indeed the disintegrin-like/cysteine-rich domains of certain hemorrhagic toxins have been shown to be potent inhibitors of collagen-induced platelet aggregation as a result of interaction of the cysteine-rich domain with the ␣2␤1 integrin on platelets (7,8). Proteolytic degradation of capillary basement membrane structures and inhibition of platelet aggregation have...

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Section: Discussionmentioning

confidence: 99%

The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

Serrano

Kim

Wang

et al. 2006

Journal of Biological Chemistry

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“…A basic glycoprotein oxiagin with molecular mass of 49.8 kDa was also isolated from the venom of N. oxiana [79]. Partial amino acid sequence determination has shown that oxiagin belongs to reprolysins, a subfamily of animal metalloproteinases possessing a characteristic multidomain structure.…”

Section: Proteins Influencing Complement Systemmentioning

confidence: 99%

Non-Lethal Polypeptide Components in Cobra Venom

Utkin

Osipov²

2007

CPD

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Snakes from several genera (mostly from Naja genus) belonging to the Elapidae family are usually named cobras. The effect of cobra bites is mainly neurotoxic. This is explained by the presence of highly potent alpha-neurotoxin in their venoms. The other two highly toxic components of cobra venoms are cytotoxins and phospholipases A(2). These three types of toxins constitute a major part of cobra venom. They have attracted the attention of researchers for many years and have been very well studied and thoroughly described. However cobra venoms contain also many other less abundant components which possess very low toxicity or even are not toxic at all. These components, mostly proteins, belong to different structural and functional types, and the reason for their presence in the venom is not always evident. Some of them are known for many years (e.g., nerve growth factor and cobra venom factor); others (e.g., cysteine rich secretory proteins, CRISPs) were discovered only recently. There are non-lethal proteins with unique biological activities that can be used as biochemical tools, while others may be regarded as potential leads for drug design. This review is the first attempt to systemize the available data on non-lethal components of cobra venom.

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“…Snake venoms consist of complex mixtures of proteins that affect different systems in the human organism, including the CS [ 1 , 14 , 15 , 29 ]. Venoms of snakes belonging to the Crotalidae and Viperidae families contain a variety of proteins that modulate the CS activity [ 30 ]. These molecules may directly cleave CS proteins such as C2, C3, and C4 and stabilize the C3-convertase of the CS-AP, which in turn amplifies the activation cascade [ 13 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Bothrops snake venoms and their isolated toxins, an L-amino acid oxidase and a serine protease, modulate human complement system pathways

Ayres

Récio

Burin

et al. 2015

J Venom Anim Toxins Incl Trop Dis

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BackgroundActivation of the complement system plays an important role in the regulation of immune and inflammatory reactions, and contributes to inflammatory responses triggered by envenomation provoked by Bothrops snakes. The present study aimed to assess whether Bothrops jararacussu and Bothrops pirajai crude venoms and their isolated toxins, namely serine protease (BjussuSP-I) and L-amino acid oxidase (BpirLAAO-I), modulate human complement system pathways.MethodsLyophilized venom and toxin samples solubilized in phosphate buffered saline were diluted in appropriate buffers to evaluate their hemolytic activity on the alternative and classical pathways of the complement system. Venom- and toxin-treated normal human serum was added to the erythrocyte suspension, and the kinetic of hemolysis was measured spectrophotometrically at 700 nm. The kinetic 96-well microassay format was used for this purpose. We determined the t½ values (time required to lyse 50 % of target erythrocytes), which were employed to calculate the percentage of inhibition of the hemolytic activity promoted by each sample concentration. To confirm complement system activation, complement-dependent human neutrophil migration was examined using the Boyden chamber model.ResultsAt the highest concentration tested (120 μg/mL), B. jararacussu and B. pirajai crude venoms inhibited the hemolytic activity of the classical pathway (65.3 % and 72.4 %, respectively) more strongly than they suppressed the hemolytic activity of the alternative pathway (14.2 and 13.6 %, respectively). BjussuSP-I (20 μg/mL) did not affect the hemolytic activity of the classical pathway, but slightly decreased the hemolytic activity of the alternative pathway (13.4 %). BpirLAAO-I (50 μg/mL) inhibited 24.3 and 12.4 % of the hemolytic activity of the classical and alternative pathways, respectively. Normal human serum treated with B. jararacussu and B. pirajai crude venoms induced human neutrophil migration at a level similar to that induced by zymosan-activated normal human serum.ConclusionTogether, the results of the kinetics of hemolysis and the neutrophil chemotaxis assay suggest that pre-activation of the complement system by B. jararacussu and B. pirajai crude venoms consumes complement components and generates the chemotactic factors C3a and C5a. The kinetic microassay described herein is useful to assess the effect of venoms and toxins on the hemolytic activity of the complement system.

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Oxiagin from the Naja oxiana cobra venom is the first reprolysin inhibiting the classical pathway of complement

Cited by 27 publications

References 24 publications

The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

Non-Lethal Polypeptide Components in Cobra Venom

Bothrops snake venoms and their isolated toxins, an L-amino acid oxidase and a serine protease, modulate human complement system pathways

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