Activated protein C cleaves factor VIIIa

Stable Identifier
R-HSA-5607002
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Activated Protein C (APC) is best known for its anticoagulant activity, the proteolytic inactivation of FVa and FVIIIa on negatively charged phospholipid membranes. This is enhanced by cofactors protein S and factor V (Rosing et al. 1995, Norstrom et al. 2006).

APC inactivates FVIIIa (Regan et al. 1994) with a mechanism similar to its inactivation of FVa. FVIIIa is cleaved by APC at Arg355 (336 if numbering excludes signal peptide) in the A1 subunit and at Arg581 (562 if numbering excludes signal peptide) in the A2 subunit (O'Brien et al. 2000, Manithody et al. 2003). The Arg355 cleavage is 6-fold faster than the Arg581 cleavage but does not fully inactivate factor VIIIa if dissociation of the A2 subunit is blocked (Gale et al. 2008). Protein S and Factor V (but not FVa) enhance the inactivation of FVIIIa by APC (O'Brien et al. 2000). Protein S and factor V both enhance cleavage at both sites, more so at Arg581 (Gale et al. 2008).

The A2 subunit of FVIIIa spontaneously dissociates, inactivating FVIIIa with a half-life of about 2 min (Fay et al. 1991).

By acting on FVa and FVIIIa Protein C down-regulates both primary and secondary thrombin formation, delaying clot formation and diminishing activation of TAFI, enhanced susceptibility of the clot to fibrinolysis, respectively. The latter effects of APC on secondary thrombin formation is sometimes referred to as APC’s profibrinolytic effect (Bajzar et al. 1996).

Literature References
PubMed ID Title Journal Year
8144529 Factor IXa protects factor VIIIa from activated protein C. Factor IXa inhibits activated protein C-catalyzed cleavage of factor VIIIa at Arg562

Regan, LM, Lamphear, BJ, Huggins, CF, Walker, FJ, Fay, PJ

J. Biol. Chem. 1994
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
serine-type endopeptidase activity of Activated protein C:Protein S [plasma membrane]
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Activity
This event is regulated
Orthologous Events
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Created