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Blood, 16 July 2009, Vol. 114, No. 3, pp. 686-692.
Prepublished online as a Blood First Edition Paper on April 13, 2009; DOI 10.1182/blood-2009-02-202663.
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Submitted February 2, 2009
Accepted April 3, 2009
Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations
Mettine H.A. Bos, Michael Boltz, Liam St. Pierre, Paul P. Masci, John de Jersey, Martin F. Lavin, and Rodney M. Camire*
Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia & The University of Pennsylvania, School of Medicine, Philadelphia, PA, United States
Queensland Institute of Medical Research, Brisbane, Australia
Faculty of Health Sciences, University of Queensland, Brisbane, Australia
University of Queensland School of Chemistry and Molecular Biosciences, Brisbane, Australia
University of Queensland Centre for Clinical Research, Brisbane, Australia
* Corresponding author; email: rcamire{at}mail.med.upenn.edu.
Venomous snakes produce an array of toxic compounds, including procoagulants to defend themselves and incapacitate prey. The Australian snake Pseudonaja textilis has a venom-derived prothrombin activator homologous to coagulation factors V (FV) and Xa (FXa). Here we show that the FV component (pt-FV) has unique biological properties which subvert the normal regulatory restraints intended to restrict an unregulated procoagulant response. Unlike human-FV, recombinant pt-FV is constitutively active and does not require proteolytic processing to function. Sequence comparisons show that it has shed a large portion of the central B-domain including residues that stabilize the inactive procofactor state. Remarkably, pt-FV functions in the absence of anionic membranes as it binds snake-FXa with high affinity in solution. Furthermore, despite cleavage in the heavy chain, pt-FV is functionally resistant to the anticoagulant, activated protein C. We speculate this stability is due to noncovalent interactions and/or a unique disulfide bond in pt-FV linking the heavy and light chains. Taken together these findings provide a biochemical rationale for the strong procoagulant nature of venom prothrombinase. Furthermore, they illustrate how regulatory mechanisms designed to limit the hemostatic response can be uncoupled to provide a sustained and disseminated procoagulant stimulus for use as a biological toxin.
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