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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-02-202663v1 114/3/686    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Bos, M. H. A. Articles by Camire, R. M. PubMed PubMed Citation Articles by Bos, M. H. A. Articles by Camire, R. M. Related Collections Thrombosis and Hemostasis Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations Mettine H. A. Bos1, Michael Boltz1, Liam St. Pierre2, Paul P. Masci3, John de Jersey4, Martin F. Lavin2,5, and Rodney M. Camire1 1 Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia; 2 Queensland Institute of Medical Research, Brisbane, Australia; and 3 Faculty of Health Sciences, 4 School of Chemistry and Molecular Biosciences, and 5 Centre for Clinical Research, University of Queensland, Brisbane, Australia 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 biologic properties that 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 activated protein C, an anticoagulant. We speculate this stability is the result of 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, disseminated procoagulant stimulus for use as a biologic toxin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Clinical relevance of brown snake (Pseudonaja spp) factor V escaping hemostatic regulation Geoffrey K. Isbister, Fiona E. Scorgie, Michael Seldon, and Lisa F. Lincz Blood 2009 114: 2563. [Full Text] [PDF] Response: Response to "Clinical relevance of brown snake (Pseudonaja spp) factor V escaping hemostatic regulation" Mettine H. A. Bos, Michael Boltz, Liam St. Pierre, Paul P. Masci, John de Jersey, Martin F. Lavin, and Rodney M. Camire Blood 2009 114: 2563-2564. [Full Text] [PDF] This article has been cited by other articles: G. K. Isbister, F. E. Scorgie, M. Seldon, and L. F. Lincz Clinical relevance of brown snake (Pseudonaja spp) factor V escaping hemostatic regulation Blood, September 17, 2009; 114(12): 2563 - 2563. [Full Text] [PDF] M. H. A. Bos, M. Boltz, L. St. Pierre, P. P. Masci, J. de Jersey, M. F. Lavin, and R. M. Camire Response: Response to "Clinical relevance of brown snake (Pseudonaja spp) factor V escaping hemostatic regulation" Blood, September 17, 2009; 114(12): 2563 - 2564. [Full Text] [PDF]

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