Inhibition of platelet aggregation by the recombinant cysteine-rich domain of the hemorrhagic snake venom metalloproteinase, atrolysin A.
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.
Jia
L G
LG
Department of Microbiology, University of Virginia Health Sciences Center, Charlottesville, Virginia, 22908, USA.
Wang
X M
XM
Shannon
J D
JD
Bjarnason
J B
JB
Fox
J W
JW
D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003435:Crotalid Venoms / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D003545:Cysteine / Q000737:chemistry; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D008969:Molecular Sequence Data; D010974:Platelet Aggregation / Q000187:drug effects*; D017434:Protein Structure, Tertiary / Q000235:genetics; D038981:Receptors, Collagen; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D018411:Spodoptera
D003435:Crotalid Venoms; D017931:DNA Primers; D018076:DNA, Complementary; D016023:Integrins; D038981:Receptors, Collagen; D011994:Recombinant Proteins; D008666:Metalloendopeptidases; C044577:atrolysin A; D003545:Cysteine