Factor Va also decreases the Km of the reaction by enhancing the binding of prothrombin to the prothrombinase complex.
Factor Va strengthens the affinity of Factor Xa for the membrane and also increases the kcat of Factor Xa for prothrombin. Further, membrane-bound Factor Va provides a strong catalytic advantage to the prothrombinase complex. Factor Xa and Factor Va interact tightly with each other when associated on the plasma membrane. When associated with the prothrombinase complex, the catalytic efficiency of Factor Xa is increased 300,000-fold compared to its efficiency alone. Assembly of the prothrombinase complex is calcium dependent. Once bound to the plasma membrane, Factor Xa and Factor Va rapidly associate in a 1:1 stoichiometric ratio to form the prothrombinase complex. Both Factor Xa and Factor Va associate with the membrane via their light chains, with Factor Xa binding via its Gla-domain in a calcium-dependent manner and Factor Va via its C2 and C1 domains. Both Factor Xa and Va bind to the membrane independently of each other, but they both bind to mutually exclusive binding sites. Activated Factor Xa and Factor Va bind to the plasma membranes of a variety of different cell types, including monocytes, platelets, and endothelial cells.
Prothrombinase assembly begins with the binding of Factor Xa and Factor Va to negatively charged phospholipids on plasma membranes. The light and heavy chains of Factor Va are linked via a divalent metal ion, such as calcium. Following cleavage, Factor Va contains a heavy chain, composed of the A1 and A2 domains and a light chain, consisting of the A3, C1, and C2 domains. Other proteases also activate Factor V, but this cleavage is primarily carried out by thrombin. Thrombin activates Factor V by cleaving off the B domain. The activation peptide is released when Factor X is activated to Factor Xa, but the heavy and light chains remain covalently linked following activation.įactor V circulates as a single-chain procofactor which contains six domains, A1-A2-B-A3-C1-C2. The intrinsic tenase complex is composed of both Factor IXa and Factor VIIIa. Factor X can be activated by both the factor VIIa- tissue factor complex of the extrinsic coagulation pathway and by the tenase complex of the intrinsic pathway. The heavy chain consists of an N-terminal activation peptide and a serine-protease domain. The light chain contains an N-terminal γ-carboxyglutamic acid domain ( Gla domain) and two epidermal growth factor-like domains (EGF1 and EGF2). The inactive zymogen Factor X consists of two chains, a light chain (136 residues) and a heavy chain (306 residues). Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.Īctivation of protein precursors īoth Factor X and Factor V circulate in the blood as inactive precursors prior to activation by the coagulation cascade. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 10 5-fold faster than can Factor Xa alone.
Although it has been shown that Factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg 271 and the other after Arg 320. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. The prothrombinase complex catalyzes the conversion of prothrombin (Factor II), an inactive zymogen, to thrombin (Factor IIa), an active serine protease. The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex consists of the serine protease, Factor Xa, and the protein cofactor, Factor Va.
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