Insights into the mechanism of haemorrhage caused by snake venom metalloproteinases

Kamiguti, Aura S.; Hay, C. R. M.; Theakston, R.D.G.; Zuzel, Mirko

doi:10.1016/0041-0101(96)00017-7

Cited by 208 publications

(130 citation statements)

References 77 publications

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“…Three PIII SVMPs, jararhagin from B. jararaca venom, atrolysin A from C. atrox venom, and kaouthiagin from Naja kaouthia venom, have been demonstrated to bind and/or proteolytically cleave VWF (9,10,32). In the case of kaouthiagin, the site of cleavage in VWF was identified at Pro 708 -Asp 709 in the C-terminal hinge region of the VWA1 domain (32).…”

Section: Discussionmentioning

confidence: 99%

“…The PIII SVMP jararhagin has been demonstrated to bind to and cleave VWF and the integrin ␣2␤1 (9). In both cases binding to these proteins resulted in proteolytic cleavage of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…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 been considered to be the key features underlying the hemorrhagic potency of PIII SVMP hemorrhagic toxins (5,9). Similarly recent studies from our laboratory demonstrated the ability of natural disintegrinlike/cysteine-rich domains processed from PIII SVMPs, as well as a recombinant cysteine-rich domain based on the structure from the PIII SVMP atrolysin A proteinase from Crotalus atrox venom, to support the interaction of the PIII SVMPs with von Willebrand factor (10).…”

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confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…In jararhagin-treated platelets, no alterations of gpIb could be detected either by flow cytometry or by immunoprecipitation (44). This indicated that jararhagin inhibition of platelet responses to the ristocetin/ vWF complex may have been due to some effect on the multimeric plasma protein, vWF.…”

Section: Venom MDC Enzymes and Platelet Functionmentioning

confidence: 66%

“…The 225-kDa vWF subunit contains the Val 449 -Lys 728 N-terminal domain responsible for ristocetin-induced binding to platelet gpIb, and one binding site for platelet α IIb ß 3 integrin containing the C-terminal RGDS 1744-1747 sequence (45). We have shown that the treatment of vWF with jararhagin resulted in the proteolysis of vWF subunits in the N-terminal half of the molecule which contains the platelet gpIb binding site (44). Thus, jararhagin inhibited platelet responses to ristocetin by cleaving the ligand vWF, with loss of the gpIb binding site.…”

Section: Venom MDC Enzymes and Platelet Functionmentioning

confidence: 99%

Snake venom metalloproteinases and disintegrins: interactions with cells

Kamiguti

Zuzel

Theakston

1998

Braz J Med Biol Res

104

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Metalloproteinases and disintegrins are important components of most viperid and crotalid venoms. Large metalloproteinases referred to as MDC enzymes are composed of an N-terminal Metalloproteinase domain, a Disintegrin-like domain and a Cys-rich C-terminus. In contrast, disintegrins are small non-enzymatic RGD-containing cysteine-rich polypeptides. However, the disintegrin region of MDC enzymes bears a high degree of structural homology to that of the disintegrins, although it lacks the RGD motif. Despite these differences, both components share the property of being able to recognize integrin cell surface receptors and thereby to inhibit integrin-dependent cell reactions. Recently, several membrane-bound MDC enzymes, closely related to soluble venom MDC enzymes, have been described in mammalian cells. This group of membrane-anchored mammalian enzymes is also called the ADAM family of proteins due to the structure revealing A Disintegrin And Metalloproteinase domains. ADAMs are involved in the shedding of molecules from the cell surface, a property which is also shared by some venom MDC enzymes.

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Metal‐ion‐ and pH‐induced conformational changes of acutolysin D from Agkistrodon acutus venom probed by fluorescent spectroscopy

Liu

et al. 2004

Biopolymers

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Acutolysin D isolated from the venom of Agkistrodon acutus is a protein of 44 kDa with marked hemorrhagic and proteolytic activities. The metal-ion- and pH-induced conformational changes of acutolysin D have been studied by following fluorescence and activity measurements. Here we provide evidence for the fact that native holo-acutolysin D adopts two different conformations, native state a, stable in the weak acidic pH range from 5.5 to 7.0 with low activity, and native state b, stable in the weak alkaline pH range from 8.0 to 9.0 with high activity. Holo-acutolysin D has an optimum pH of 9.0 for caseinolytic activity and a maximum fluorescence at pH 9.0. The protein adopts the most stable conformation at pH 9.0. The addition of 1 mM Zn(2+) shifts both the alkali-induced unfolding transition curve and the alkali-induced inactivation curve toward higher pH value but has little effect on the acid-induced unfolding transition curve. No obvious effects on the pH-induced unfolding transition curve and the pH-dependent activity curve have been observed after the addition of 1 mM Ca(2+) to holo-acutolysin D. The results indicate that Zn(2+) is essential for its CA, while Ca(2+) is not essential for its CA. Removal of Ca(2+) and Zn(2+) from the protein enhances its sensitivity to pH and significantly reduces its overall stability during acid-induced denaturation. The kinetic results of the demetalization of holo-acutolysin D show that the demetalization rate constant K(1) for a slower reaction linearly decreases with the pH increase from 5.0 to 9.0, while K(2) for the faster reaction linearly increases with the pH change from 5.0 to 7.0. It is also evident from the present work that the free Zn(2+)-induced inactivation in the pH range from 8.0 to 9.0 should be attributed to the effect of Zn(OH)(2) precipitation on the protein.

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Insights into the mechanism of haemorrhage caused by snake venom metalloproteinases

Cited by 208 publications

References 77 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

Snake venom metalloproteinases and disintegrins: interactions with cells

Metal‐ion‐ and pH‐induced conformational changes of acutolysin D from Agkistrodon acutus venom probed by fluorescent spectroscopy

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