Reactome | factor Va + factor Xa -> Va:Xa complex (prothrombinase)

factor Va + factor Xa -> Va:Xa complex (prothrombinase)

Stable Identifier

R-HSA-140686

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

ReviewStatus

5/5

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factor Va + factor Xa -> Va:Xa complex (prothrombinase)

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In the presence of calcium ions (Ca²⁺), factor Va (FVa) and factor Xa (FXa) associate on a membrane surface to form the prothrombinase complex, FVa:FXa. Formation of this complex significantly enhances the proteolytic activity of FXa on prothrombin (FII) (Mann KG et al., 1988; reviewed by Stoilova-McPhie S, 2021). The activation of both FV and FX, as well as the formation of the FVa:FXa complex, are crucial steps in the initiation, amplification, and propagation phases of coagulation. During the initiation phase, zymogen FX associates with the tissue factor (TF):FVIIa complex, which converts FX to FXa on the membrane surfaces of TF-bearing cells, such as fibroblasts and pericytes (Norledge BV et al., 2003; Venkateswarlu D et al., 2003; reviewed in Vadivel K & Bajaj SP, 2012). In the amplification and propagation phases, large amounts of FXa are generated by the FIXa:FVIIIa complex (the tenase complex), which converts FX to FXa on the platelet surface (reviewed by Hoffman M 2003; O'Donnell JS et al., 2019). Activation of procofactor FV is catalyzed by both FXa and trace amounts of thrombin during the initiation phase of coagulation (Monkovic DD & Tracy PB, 1990; Brummel KE et al., 2002; Orfeo T et al., 2004; Schuijt TJ et al., 2013; reviewed by Camire RM & Bos MHA, 2009). Subsequently, large amounts of thrombin produced during the amplification and propagation phases further convert FV to FVa (Corral-Rodríguez MA et al., 2011; reviewed by Hoffman M 2003; O'Donnell JS et al., 2019). Proteolytic cleavage of FV removes the inhibitory B domain, exposing FXa-binding sites within the A2 domain of FV (Steen M et al., 2002, 2008; Kalafatis M & Beck DO, 2002; Gale AJ et al., 2007; Bos MHA & Camire RM, 2012; Bunce MW et al., 2013; Schreuder M et al., 2019; Ruben EA et al., 2021, 2022; Di Cera E 2022). This cleavage, specifically at Arg1573, increases the binding affinity of FVa for FXa with dissociation constant (Kd) value within the nanomolar range (Steen M & Dahlbäck B 2002; Bunce MW et al., 2013; Gantseva AR et al., 2024). Additionally, FVa binding to the protease domain of FXa is believed to optimize the enzyme's catalytic activity and substrate binding (Yang L et al., 2008; Di Cera E 2022; Ruben EA et al., 2022). The presence of negatively charged phospholipid in the membrane greatly facilitates formation of the FVa:FXa complex, a feature that may contribute to FVa:FXa localization (Qureshi SH et al., 2009; Gantseva AR et al., 2024; reviewed by Protty MB et al., 2022), as such phospholipids are normally found on the cytosolic face of the plasma membrane (Devaux PF 1992), but could be exposed to the extracellular space following platelet activation or mechanical injury to endothelial cells. The calcium-dependent binding of FVa to phosphatidylserine (PS)-rich membranes is mediated by the C1 and C2 domains of FVa (Peng W et al., 2005; Majumder R et al., 2008; Ruben EA et al., 2022; Ohkubo YZ et al., 2024), while FXa binds via its Gla domain (Qureshi SH et al., 2009; Muller MP et al., 2017; Paul D & Morrissey JH, 2022; Ruben EA et al., 2022).

Literature References

PubMed ID	Title	Journal	Year
35427420	Cryo-EM structure of the prothrombin-prothrombinase complex Ruben, EA, Summers, B, Rau, MJ, Fitzpatrick, JAJ, Di Cera, E	Blood	2022
19378973	Membrane-dependent interaction of factor Xa and prothrombin with factor Va in the prothrombinase complex Qureshi, SH, Yang, L, Manithody, C, Rezaie, AR	Biochemistry	2009
31102425	Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding Schreuder, M, Reitsma, PH, Bos, MHA	J Thromb Haemost	2019
12384508	Defining the factor Xa-binding site on factor Va by site-directed glycosylation Steen, M, Villoutreix, BO, Norstrøm, EA, Yamazaki, T, Dahlbäck, B	J Biol Chem	2002
3052293	Cofactor proteins in the assembly and expression of blood clotting enzyme complexes Mann, KG, Jenny, RJ, Krishnaswamy, S	Annu Rev Biochem	1988
12570161	Factor Va-factor Xa interactions: molecular sites involved in enzyme:cofactor assembly Steen, M	Scand J Clin Lab Invest Suppl	2002
36349261	Cryo-EM structures of coagulation factors Di Cera, E, Mohammed, BM, Pelc, LA, Stojanovski, BM	Res Pract Thromb Haemost	2022