Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Bos MH,Boltz M,St Pierre L,Masci PP,de Jersey J,Lavin MF,Camire RM

doi

10.1182/blood-2009-02-202663

subject

Has Abstract

pub_date

2009-07-16 00:00:00

pages

686-92

issue

3

eissn

0006-4971

issn

1528-0020

pii

blood-2009-02-202663

journal_volume

114

pub_type

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