Figure 2.
Figure 2. Schematic representation of APC and APC/PS-dependent inactivation of factors Va and VIIIa. (A) Factor V is converted into factor Va by thrombin or factor Xa by cleavages at Arg709, Arg1018, and Arg1545. This results in the loss of the B domain and formation of the factor Va heterodimer consisting of a heavy (A1-A2) and a light (A3-C1-C2) chain, coupled by a single calcium ion (Ca), tightly bound between the A1 and A3 domains. The C2 subunit of the light chain binds to negatively charged phospholipid membranes. Factor Va is inactivated by activated protein C (APC) cleavage at 3 sites in the heavy chain: Arg306, Arg506, and Arg679. However, the pattern of cleavage depends on whether protein S (PS) is absent (top) or present (bottom). Only cleavage at Arg306, which bisects the A1 and A2 domain, results in complete loss of factor Va activity. In the absence of PS, rapid initial cleavage at Arg506 occurs, resulting in a molecule with intermediate activity. This cleavage is slow and seems to be required for the optimum exposure of Arg306 (red box). The presence of PS increases the affinity of APC for the membrane surface (arrows) and seems to relocate the active site of APC for preferential cleavage at Arg306 (the distance of closest approach is indicated). This augments the rate of Arg306 cleavage approximately 20-fold, and rapidly inactivates factor Va. (B) Factor VIII is activated by thrombin through cleavage at Arg372 (which bisects the contiguous A1-A2 domains), Arg740, and Arg1689 (which liberates the B region). Factor VIIIa is a heterotrimer consisting of A1 and A2 domains and the light chain (A3-C1-C2). The A2 associates with the A1 domain via weak electrostatic interactions (dotted line), with rapid dissociation at low concentrations. APC inactivates factor VIIIa by a similar mechanism to factor Va, although the APC cleavage sites are Arg336 and Arg562. Complete inactivation of factor VIIIa is correlated with cleavage at Arg562. In the absence of PS (top), Arg336 is cleaved at a higher rate. In the presence of PS and fragments derived from the “B” region of factor V, cleavage at Arg562 is accelerated and factor VIIIa is inactivated more rapidly.

Schematic representation of APC and APC/PS-dependent inactivation of factors Va and VIIIa. (A) Factor V is converted into factor Va by thrombin or factor Xa by cleavages at Arg709, Arg1018, and Arg1545. This results in the loss of the B domain and formation of the factor Va heterodimer consisting of a heavy (A1-A2) and a light (A3-C1-C2) chain, coupled by a single calcium ion (Ca), tightly bound between the A1 and A3 domains. The C2 subunit of the light chain binds to negatively charged phospholipid membranes. Factor Va is inactivated by activated protein C (APC) cleavage at 3 sites in the heavy chain: Arg306, Arg506, and Arg679. However, the pattern of cleavage depends on whether protein S (PS) is absent (top) or present (bottom). Only cleavage at Arg306, which bisects the A1 and A2 domain, results in complete loss of factor Va activity. In the absence of PS, rapid initial cleavage at Arg506 occurs, resulting in a molecule with intermediate activity. This cleavage is slow and seems to be required for the optimum exposure of Arg306 (red box). The presence of PS increases the affinity of APC for the membrane surface (arrows) and seems to relocate the active site of APC for preferential cleavage at Arg306 (the distance of closest approach is indicated). This augments the rate of Arg306 cleavage approximately 20-fold, and rapidly inactivates factor Va. (B) Factor VIII is activated by thrombin through cleavage at Arg372 (which bisects the contiguous A1-A2 domains), Arg740, and Arg1689 (which liberates the B region). Factor VIIIa is a heterotrimer consisting of A1 and A2 domains and the light chain (A3-C1-C2). The A2 associates with the A1 domain via weak electrostatic interactions (dotted line), with rapid dissociation at low concentrations. APC inactivates factor VIIIa by a similar mechanism to factor Va, although the APC cleavage sites are Arg336 and Arg562. Complete inactivation of factor VIIIa is correlated with cleavage at Arg562. In the absence of PS (top), Arg336 is cleaved at a higher rate. In the presence of PS and fragments derived from the “B” region of factor V, cleavage at Arg562 is accelerated and factor VIIIa is inactivated more rapidly.

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