Rhinocetin, a Venom-derived Integrin-specific Antagonist Inhibits Collagen-induced Platelet and Endothelial Cell Functions

Autor: Jonathan M. Gibbins, E. Gail Hutchinson, Andrew B. Bicknell, Ronald G. Stanley, Abeer Dannoura, Marfoua S. Ali, Sakthivel Vaiyapuri, Robert A. Harrison
Rok vydání: 2012
Předmět:
Integrins
Platelet Aggregation
Rhinocetin
Biochemistry
Collagen receptor
Cell Movement
Sequence Analysis
Protein
Viperidae
Toxins
Platelet
Cells
Cultured
0303 health sciences
030302 biochemistry & molecular biology
3. Good health
Cell biology
Endothelial stem cell
Integrin alpha M
Collagen
Integrin alpha2beta1
Protein Binding
Platelets
Blood Platelets
Molecular Sequence Data
Integrin
Viper Venoms
Bitis Gabonica Rhinoceros
Biology
03 medical and health sciences
Snaclec
Hematologic Agents
Cell Adhesion
Human Umbilical Vein Endothelial Cells
Animals
Humans
Endothelium
Amino Acid Sequence
Calcium Signaling
Platelet activation
Protein Structure
Quaternary
Blood Coagulation
Molecular Biology
Cell Proliferation
030304 developmental biology
Hemostasis
Sequence Homology
Amino Acid
Secretory Vesicles
Endothelial Cells
Fibrinogen binding
Cell Biology
Venom Protein
Venom
biology.protein
Integrin α2β1
Zdroj: The Journal of Biological Chemistry
ISSN: 0021-9258
DOI: 10.1074/jbc.m112.381483
Popis: Background: Snaclecs affect the hemostasis of snakebite victims upon envenomation. Results: Rhinocetin, a novel snaclec, inhibits integrin α2β1-dependent functions of human platelets and endothelial cells. Conclusion: The actions of rhinocetin are consistent with hemorrhagic symptoms upon envenomation. Significance: Due to its inhibitory actions on integrin α2β1, rhinocetin may have potential diagnostic and therapeutic values.
Snaclecs are small non-enzymatic proteins present in viper venoms reported to modulate hemostasis of victims through effects on platelets, vascular endothelial, and smooth muscle cells. In this study, we have isolated and functionally characterized a snaclec that we named “rhinocetin” from the venom of West African gaboon viper, Bitis gabonica rhinoceros. Rhinocetin was shown to comprise α and β chains with the molecular masses of 13.5 and 13 kDa, respectively. Sequence and immunoblot analysis of rhinocetin confirmed this to be a novel snaclec. Rhinocetin inhibited collagen-stimulated activation of human platelets in a dose-dependent manner but displayed no inhibitory effects on glycoprotein VI (collagen receptor) selective agonist, CRP-XL-, ADP-, or thrombin-induced platelet activation. Rhinocetin antagonized the binding of monoclonal antibodies against the α2 subunit of integrin α2β1 to platelets and coimmunoprecipitation analysis confirmed integrin α2β1 as a target for this venom protein. Rhinocetin inhibited a range of collagen-induced platelet functions such as fibrinogen binding, calcium mobilization, granule secretion, aggregation, and thrombus formation. It also inhibited integrin α2β1-dependent functions of human endothelial cells. Together, our data suggest rhinocetin to be a modulator of integrin α2β1 function and thus may provide valuable insights into the role of this integrin in physiological and pathophysiological scenarios, including hemostasis, thrombosis, and envenomation.
Databáze: OpenAIRE
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