ArticleProtein science : a publication of the Protein Society2002
Interdomain engineered disulfide bond permitting elucidation of mechanisms of inactivation of coagulation factor Va by activated protein C.
Article in Protein science : a publication of the Protein Society, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 47 citations in OpenAlex.
- Impaired factor V-related anticoagulant mechanisms and deep vein thrombosis associated with A2086D and W1920R mutations.Blood advances · 2023Article
- An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice.Blood advances · 2022Article
- An engineered factor Va prevents bleeding induced by direct-acting oral anticoagulants by different mechanisms.Blood advances · 2020Article
- Safety, Stability and Pharmacokinetic Properties of (super)Factor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding.Pharmaceutical research · 2016Article
- Improved coagulation and haemostasis in haemophilia with inhibitors by combinations of superFactor Va and Factor VIIa.Thrombosis and haemostasis · 2016Article
- Acquired hemophilia A: emerging treatment options.Journal of blood medicine · 2015Review
- Improved hemostasis in hemophilia mice by means of an engineered factor Va mutant.Journal of thrombosis and haemostasis : JTH · 2014Article
- An engineered factor Va prevents bleeding induced by anticoagulant wt activated protein C.PloS one · 2014Article
- Biological Insights into Therapeutic Protein Modifications throughout Trafficking and Their Biopharmaceutical Applications.International journal of cell biology · 2013Article
- Factor V is an anticoagulant cofactor for activated protein C during inactivation of factor Va.Pathophysiology of haemostasis and thrombosis · 2010Article
- Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations.Blood · 2009Article
- Article
- Prothrombin amino terminal region helps protect coagulation factor Va from proteolytic inactivation by activated protein C.Thrombosis and haemostasis · 2009Article
- Mapping of the factor Xa binding site on factor Va by site-directed mutagenesis.The Journal of biological chemistry · 2008Article
- Detailed mechanisms of the inactivation of factor VIIIa by activated protein C in the presence of its cofactors, protein S and factor V.The Journal of biological chemistry · 2008Article
- Article
- Progress in the understanding of the protein C anticoagulant pathway.International journal of hematology · 2004Review
- DSDBASE: a consortium of native and modelled disulphide bonds in proteins.Nucleic acids research · 2004Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Procoagulant factor Va (FVa) is inactivated via limited proteolysis at three Arg residues in the A2 domain by the anticoagulant serine protease, activated protein C (APC). Cleavage by APC at Arg306 in FVa causes dissociation of the A2 domain from the heterotrimeric A1:A2:A3 structure and complete loss of procoagulant activity. To help distinguish inactivation mechanisms involving A2 domain dissociation from inactivation mechanisms involving unfavorable changes in factor Xa (FXa) affinity, we used our FVa homology model to engineer recombinant FVa mutants containing an interdomain disulfide bond (Cys609-Cys1691) between the A2 and A3 domains (A2-SS-A3 mutants) in addition to cleavage site mutations, Arg506Gln and Arg679Gln. SDS-PAGE analysis showed that the disulfide bond in A2-SS-A3 mutants prevented dissociation of the A2 domain. In the absence of A2 domain dissociation from the A1:A2:A3 trimer, APC cleavage at Arg306 alone caused a sevenfold decrease in affinity for FXa, whereas APC cleavages at Arg306, Arg506, and Arg679 caused a 70-fold decrease in affinity for FXa and a 10-fold decrease in the k(cat) of the prothrombinase complex for prothrombin without any effect on the apparent K(m) for prothrombin. Therefore, for FVa inactivation by APC, dissociation of the A2 domain may provide only a modest final step, whereas the critical events are the cleavages at Arg506 and Arg306, which effectively inactivate FVa before A2 dissociation can take place. Nonetheless, for FVa Leiden (Gln506-FVa) inactivation by APC, A2 domain dissociation may become mechanistically important, depending on the ambient FXa concentration.
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