Inhibition of Platelet Aggregation by the Recombinant Cysteine-Rich Domain of the Hemorrhagic Snake Venom Metalloproteinase, Atrolysin A

• Published in: Archives of biochemistry and biophysics Vol. 373; no. 1; pp. 281 - 286
• Main Authors: Jia, Li-Guo, Wang, Xiao-Ming, Shannon, John D., Bjarnason, Jon B., Fox, Jay W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2000
• Subjects: Amino Acid Sequence; Animals; Baculoviridae - genetics; Base Sequence; Binding Sites; Blood Platelets - drug effects; Blood Platelets - metabolism; Cell Line; Crotalid Venoms - chemistry; Crotalid Venoms - genetics; Crotalid Venoms - toxicity; Cysteine - chemistry; cysteine-rich domain; DNA Primers - genetics; DNA, Complementary - genetics; Gene Expression; Humans; In Vitro Techniques; Integrins - metabolism; Metalloendopeptidases - chemistry; Metalloendopeptidases - genetics; Metalloendopeptidases - toxicity; metalloproteinases; Molecular Sequence Data; platelet aggregation; Platelet Aggregation - drug effects; Protein Structure, Tertiary - genetics; Receptors, Collagen; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - toxicity; snake venoms; Spodoptera; metalloproteinases; snake venoms; cysteine-rich domain; platelet aggregation
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1006/abbi.1999.1517

The P-III class of venom metalloproteinases has, in addition to the proteinase domain, a disintegrin-like domain and a cysteine-rich domain. Recent evidence has shown that the nonproteinase domains of the P-III class of hemorrhagic metalloproteinases function in the inhibition of platelet aggregation by blocking essential procoagulant integrins on platelets. A specific role for the highly conserved cysteine-rich domain has yet to be described. In this study, we expressed the cysteine-rich domain from the hemorrhagic metalloproteinase atrolysin A and demonstrated its ability to inhibit collagen-stimulated platelet aggregation. Additionally, the cysteine-rich domain was shown to interact with MG-63 cells to inhibit adhesion to collagen I. These data suggest a functional role for the cysteine-rich domain of the P-III toxins in the observed coagulopathy by targeting the toxin to platelets and inhibiting collagen-stimulated platelet aggregation. These characteristics may function to synergistically increase the hemorrhagic effect of the toxins.