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Details on Person Coagulation factor V (FV, encoded by the F5 gene) is activat...
| Class:Id | Summation:9930791 |
|---|---|
| _displayName | Coagulation factor V (FV, encoded by the F5 gene) is activat... |
| _timestamp | 2025-01-10 22:20:08 |
| created | [InstanceEdit:9930783] Shamovsky, Veronica, 2024-12-06 |
| literatureReference | [LiteratureReference:9929742] Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein [LiteratureReference:9929749] Cryo-EM structure of coagulation factor V short [LiteratureReference:9929737] The molecular basis of factor V and VIII procofactor activation [LiteratureReference:9929746] Factor VIII and Factor V Membrane Bound Complexes [LiteratureReference:9929741] A bipartite autoinhibitory region within the B-domain suppresses function in factor V [LiteratureReference:140680] The factor V activation paradox [LiteratureReference:9822569] Cleavage requirements for activation of factor V by factor Xa [LiteratureReference:9929743] Structural architecture of the acidic region of the B domain of coagulation factor V [LiteratureReference:9930541] Restoring the procofactor state of factor Va-like variants by complementation with B-domain peptides [LiteratureReference:9930554] Major bleeding during oral anticoagulant therapy associated with factor V activation by factor Xa [LiteratureReference:9930552] Activation of human factor V by factor Xa and thrombin [LiteratureReference:9930557] Occlusion of anion-binding exosite 2 in meizothrombin explains its impaired ability to activate factor V [LiteratureReference:9930563] Activation of human factor V by meizothrombin [LiteratureReference:9930762] Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation [LiteratureReference:9930543] Cryo-EM structures of human coagulation factors V and Va [LiteratureReference:9930789] Thrombin-mediated proteolysis of factor V resulting in gradual B-domain release and exposure of the factor Xa-binding site [LiteratureReference:9930786] Novel insights into the regulation of coagulation by factor V isoforms, tissue factor pathway inhibitorα, and protein S [LiteratureReference:9930754] Thrombin functions during tissue factor-induced blood coagulation [LiteratureReference:9931602] Rethinking events in the haemostatic process: role of factor V and TFPI [LiteratureReference:9934803] Removal of B-domain sequences from factor V rather than specific proteolysis underlies the mechanism by which cofactor function is realized [LiteratureReference:9920973] Natural anticoagulant discovery, the gift that keeps on giving: finding FV-Short [LiteratureReference:9934790] The C-terminus of tissue factor pathway inhibitor-α inhibits factor V activation by protecting the Arg1545 cleavage site [LiteratureReference:9934792] Regulation of factor V and factor V-short by TFPIα: Relationship between B-domain proteolysis and binding [LiteratureReference:140650] Cofactor proteins in the assembly and expression of blood clotting enzyme complexes |
| modified | [InstanceEdit:9933738] Shamovsky, Veronica, 2025-01-03 [InstanceEdit:9934805] Shamovsky, Veronica, 2025-01-10 |
| text | Coagulation factor V (FV, encoded by the F5 gene) is activated by proteolytic cleavage at Arg737, Arg1046, and Arg1573. In the early phase of coagulation this cleavage is catalyzed by either activated factor X (FXa) or trace amounts of thrombin (FIIa) (Monkovic DD & Tracy PB, 1990; Thorelli E et al., 1997; Brummel KE et al., 2002; Orfeo T et al., 2004; Schuijt TJ et al., 2013; Maag A et al., 2022; reviewed by Camire RM & Bos MHA, 2009). Meizothrombin, an intermediate in prothrombin (FII) activation, may also contribute to the FV activation during the initiation phase (Tans G et al., 1994). However, the cleavage of FV by meizothrombin occurs at a slower rate compared to thrombin (FIIa) due to the covalent linkage of its N-terminal pro-piece, which impairs the function of anion-binding exosite 2 (ABE2), a critical exosite for efficient FV activation (Bradford HN & Krishnaswamy S 2019). FV circulates in the blood as an inactive procofactor composed of the following domains: A1-A2-B-A3-C1-C2. The B domain maintains FV in its inactive state via an electrostatic interaction between its basic region (BR) and acidic region (AR) (Bos MH & Camire RM, 2012; Camire RM, 2016; Dahlbäck B et al., 2017; Ruben EA et al., 2021; Mohammed BM et al., 2024). FV proteolysis at Arg737, Arg1046, and Arg1573, releases the inhibitory B domain, which separates the heavy FV (29–737) and light FV (1574–2224) chains (Monkovic DD & Tracy PB, 1990; Thorelli E et al., 1997; Orfeo T et al., 2004; Toso R & Camire RM 2004; Schuijt TJ et al., 2013; Maag A et al., 2022; reviewed by Camire RM & Bos MHA, 2009). The B domain of FV is cleaved sequentially, generating partially activated FVa intermediate forms that retain the acidic region (AR) (Steen M & Dahlbäck B 2002; Dahlbäck B, 2023). This process begins with cleavage at Arg737 and Arg1046, catalyzed during the initiation phase of coagulation by either activated factor X (FXa) or trace amounts of thrombin. This cleavage removes the N-terminal region of the B domain (FV (738-1046)), disrupting the inhibitory BR-AR interaction, exposing the AR, and enhancing the prothrombinase activity of FV intermediates. At this stage, partially cleaved FV intermediates are procoagulant-active but remain regulated by tissue factor pathway inhibitor α (TFPIα), which prevents full activation of FV, inhibiting its prothrombinase cofactor activity (Wood JP et al., 2013; van Doorn P et al., 2017; Petrillo T et al., 2021; Mohammed BM et al., 2024). The final cleavage at Arg1573 (catalyzed mostly by thrombin) completely removes the B domain, fully converting FV into its activated form, FVa, which exhibits high-affinity binding to FXa (Bunce MW et al., 2013; Bos MHA & Camire RM, 2012; Ruben EA et al., 2021; Mohammed BM et al., 2023, 2024). FVa binds FXa in the presence of calcium ions to form the prothrombinase complex (FVa:FXa) on the cell surface, where FVa:FXa converts factor II (FII) to thrombin (FIIa) (Mann KG et al., 1988; reviewed by Stoilova-McPhie S, 2021). This Reactome event describes the cleavage of procofactor FV (29–2224) at Arg737 and Arg1046, catalyzed by trace amounts of thrombin, producing FV intermediates during the initiation phase (Monkovic DD & Tracy PB, 1990; Brummel KE et al., 2002; Orfeo T et al., 2004; reviewed by Camire RM & Bos MHA, 2009). The N-terminal region of the inhibitory B domain, FV (738–1046), is released, while the C-terminal acidic region of the B domain remains attached to the FV light chain, forming the FV (1047–2224) polypeptide. |
| (summation) | [Reaction:9930790] factor V -> factor Va intermediate + factor V activation peptide (thrombin catalyst) [Homo sapiens] |
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