Aggretin, a novel platelet-aggregation inducer from snake (<i>Calloselasma rhodostoma</i>) venom, activates phospholipase C by acting as a glycoprotein Ia/IIa agonist

Huang, Tur‐Fu; Liu, Chao-Zong; Yang, Sheng-Hsin

doi:10.1042/bj3091021

Cited by 90 publications

(76 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also found that echicetin had a minor inhibitory effect on platelet responses to low concentrations of aggretin (data not shown). The monoclonal antibodies that had no effect on aggretin were AP-1 and 6D1 (17). Thus, the binding site for aggretin on GPIb must partly overlap with the echicetin-binding site but not with the epitopes of AP-1, 6D1, SZ-2, or Ib-23.…”

Section: Discussionmentioning

confidence: 95%

“…Several earlier studies reported proteins from the venom of C. rhodostoma that activate platelets, and it was suggested that one of these, called aggregoserpentin or aggretin, acts via ␣ 2 ␤ 1 (17). Aggretin was recently cloned, and the full amino acid sequence was established (18).…”

Section: Discussionmentioning

confidence: 99%

“…This implies that two subunits of the protein are linked together by disulfide bridges and that two heterodimers interact noncovalently to form tetramers. Aggretin aggregated platelets in a dose-dependent manner with a long lag phase as previously described (17).…”

Section: Discussionmentioning

confidence: 99%

“…Several other snake venom proteins are potent platelet activators and may act via collagen-like mechanisms. Some of these, including trimucytin from Trimeresurus mucrosquamatus (16) and aggretin from Calloselasma rhodostoma (17), have been reported to involve ␣ 2 ␤ 1 on platelets as receptor. We isolated a protein from C. rhodostoma venom that is a powerful platelet activator.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Aggretin, a Heterodimeric C-type Lectin from Calloselasma rhodostoma (Malayan Pit Viper), Stimulates Platelets by Binding to α2β1 Integrin and Glycoprotein Ib, Activating Syk and Phospholipase Cγ2, but Does Not Involve the Glycoprotein VI/Fc Receptor γ Chain Collagen Receptor

Navdaev

Clemetson

Polgár

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Aggretin, a potent platelet activator, was isolated from Calloselasma rhodostoma venom, and 30-amino acid N-terminal sequences of both subunits were determined. Aggretin belongs to the heterodimeric snake Ctype lectin family and is thought to activate platelets by binding to platelet glycoprotein ␣ 2 ␤ 1 . We now show that binding to glycoprotein (GP) Ib is also required. Aggretin-induced platelet activation was inhibited by a monoclonal antibody to GPIb as well as by antibodies to ␣ 2 ␤ 1 . Binding of both of these platelet receptors to aggretin was confirmed by affinity chromatography. No binding of other major platelet membrane glycoproteins, in particular GPVI, to aggretin was detected. Aggretin also activates platelets from Fc receptor ␥ chain (Fc␥)-deficient mice to a greater extent than those from normal control mice, showing that it does not use the GPVI/Fc␥ pathway. Platelets from Fc␥-deficient mice expressed fibrinogen receptors normally in response to collagen, although they did not aggregate, indicating that these platelets may partly compensate via other receptors including ␣ 2 ␤ 1 or GPIb for the lack of the Fc␥ pathway. Signaling by aggretin involves a dose-dependent lag phase followed by rapid tyrosine phosphorylation of a number of proteins. Among these are p72 SYK , p125 FAK , and PLC␥2, whereas, in comparison with collagen and convulxin, the Fc␥ subunit neither is phosphorylated nor coprecipitates with p72 SYK . This supports an independent, GPIb-and integrin-based pathway for activation of p72 SYK not involving the Fc␥ receptor.Platelet-collagen interactions are integral to primary hemostasis (1, 2). Resting platelets using several receptors adhering to subendothelium of damaged blood vessels are activated and spread to provide finally a new nonthrombogenic surface until vasculature regeneration occurs. Reversible binding between GPIb-V-IX 1 and von Willebrand factor, associated with collagen, is crucial to slow down the platelet (especially under high shear) so that it can bind more firmly via other receptors (3, 4). This mechanism strongly parallels that of the selectins in leukocyte adhesion (5). Another important receptor is the ␣ 2 ␤ 1 integrin, which is essential for anchoring the platelet to collagen in the subendothelium (6) and for linking to the platelet cytoskeleton to prevent the receptor being torn from the membrane by the forces that it has to withstand. Activation induces the release of storage granules and the expression of new receptors on the platelet surface (7) as well as changes in other receptors such as the fibrinogen receptor, ␣ IIb ␤ 3 , which is critical for spreading. Although GPIb-V-IX and ␣ 2 ␤ 1 also participate in signaling to the platelet interior (8, 9), recent studies, particularly in patients with platelet receptor deficiencies, have implicated GPVI/Fc␥ as a major collagen receptor for platelet activation (10 -12). Patients with platelets lacking any one of these receptors (GPIb-V-IX, ␣ 2 ␤ 1 , or GPVI/Fc␥) have increased bleeding times, and platelet adhesio...

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Aggretin, a Heterodimeric C-type Lectin from Calloselasma rhodostoma (Malayan Pit Viper), Stimulates Platelets by Binding to α2β1 Integrin and Glycoprotein Ib, Activating Syk and Phospholipase Cγ2, but Does Not Involve the Glycoprotein VI/Fc Receptor γ Chain Collagen Receptor

Navdaev

Clemetson

Polgár

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Another example of the promiscuity of C-type lectins might be the behavior of aggretin, derived from Calloselasma rhodostoma (18). Aggretin (rhodocytin) was initially reported to bind to the integrin collagen receptor ␣ 2␤1 (19) and later reported to also bind to GPIb (18). However, more recent studies with genetically engineered murine platelets that lack ␣ 2␤1 and GPVI and were stripped of GPIb by proteolysis challenge these conclusions, showing that none of these receptors is required for platelet activation by rhodocytin (20).…”

Section: Discussionmentioning

confidence: 99%

Convulxin Binds to Native, Human Glycoprotein Ibα

Kanaji¹,

Kanaji²,

Furihata³

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Convulxin (CVX), a C-type snake protein from Crotalus durissus terrificus venom, is the quintessential agonist for studies of the collagen receptor, glycoprotein VI (GPVI) and its role in platelet adhesion to collagens. In this study, CVX, purified from venom, behaves as expected, i.e. it binds to platelet GPVI and recombinant human GPVI, induces platelet aggregation and platelet prothrombinase activity, and binds uniquely to GPVI in ligand blots of SDS-denatured proteins. Nonetheless, we find that CVX has a dual specificity for both GPVI and native but not denatured human GPIb␣. First, CVX binds to human GPIb␣ expressed on the surface of CHO cells. Second, CVX binds weakly to murine platelet GPIb␣ but more strongly to human platelet GPIb␣, as evidenced by comparative binding to wild-type, GPVI(؊/؊), FcR␥ (؊/؊), and human GPIb transgenic mice. Third, the binding of CVX to human GPIb␣ is inhibited by soluble, recombinant human GPVI. Fourth, CVX binding to GPIb␣ is disrupted by phenylalanine substitutions at GPIb␣ tyrosine-276, tyrosine-278, and tyrosine-279, which also disrupts von Willebrand factor and ␣-thrombin binding to GPIb␣. Fifth, CVX binding to GPIb␣ on Chinese hamster ovary cell transfectants is inhibited by function-blocking murine monoclonal anti-GPIb␣ antibodies. Lastly, CVX fails to bind to denatured GPIb␣ in detergent extracts of platelets. Three separate preparations of CVX (two purified by the authors; one obtained commercially) produced equivalent results. These results indicate that CVX exhibits dual specificity for both native GPIb␣ and GPVI. Furthermore, the binding site on GPIb␣ for CVX may be close to that for von Willebrand factor. Therefore, a contribution of GPIb␣ to CVX-induced platelet responses needs to be carefully re-evaluated.Convulxin (CVX) 1 is a 72-kDa protein from Crotalus durissus terrificus venom that has been shown to bind strongly to the platelet-specific collagen receptor, glycoprotein VI (GPVI) (1, 2).The active protein is composed of two disulfide-linked subunits, CVX␣ (13.9 kDa) and CVX␤ (12.6 kDa), which noncovalently assemble into a tridimeric complex (␣ ␤) 3 (3). Both subunits have been cloned and sequenced and exhibit homology with the carbohydrate recognition domain of C-type lectins (4, 5).C-type snake proteins are produced in the venom of numerous true vipers and pit vipers (5). They can be composed of homodimers or heterodimers, often present in multiples, each subunit exhibiting homology to the carbohydrate recognition domain of C-type lectins. Unlike the C-type lectins, however, the subunits of the heterodimeric C-type proteins, such as CVX, do not retain the mannose or galactose recognition sequences and, thus, no longer bind carbohydrate. The ability to bind calcium is retained and may be critical for their activity.A number of the C-type viper venom proteins target platelet receptors, including the glycoprotein Ib (GPIb) complex and GPVI. The majority, including alboaggregin A (6) and alboluxin (7), exhibit dual specificity for these receptors, whereas only...

show abstract

Convulxin Induces Platelet Activation by a Tyrosine-Kinase-Dependent Pathway and Stimulates Tyrosine Phosphorylation of Platelet Proteins, Including PLCγ2, Independently of Integrin αIIbβ3

Francischetti

Ghazaleh

Reis

et al. 1998

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Aggretin, a novel platelet-aggregation inducer from snake (Calloselasma rhodostoma) venom, activates phospholipase C by acting as a glycoprotein Ia/IIa agonist

Cited by 90 publications

References 39 publications

Aggretin, a Heterodimeric C-type Lectin from Calloselasma rhodostoma (Malayan Pit Viper), Stimulates Platelets by Binding to α2β1 Integrin and Glycoprotein Ib, Activating Syk and Phospholipase Cγ2, but Does Not Involve the Glycoprotein VI/Fc Receptor γ Chain Collagen Receptor

Aggretin, a Heterodimeric C-type Lectin from Calloselasma rhodostoma (Malayan Pit Viper), Stimulates Platelets by Binding to α2β1 Integrin and Glycoprotein Ib, Activating Syk and Phospholipase Cγ2, but Does Not Involve the Glycoprotein VI/Fc Receptor γ Chain Collagen Receptor

Convulxin Binds to Native, Human Glycoprotein Ibα

Convulxin Induces Platelet Activation by a Tyrosine-Kinase-Dependent Pathway and Stimulates Tyrosine Phosphorylation of Platelet Proteins, Including PLCγ2, Independently of Integrin αIIbβ3

Contact Info

Product

Resources

About