Factor V: Dr. Jeckyll and Mr. Hyde

Kalafatis, Michael; Mann, Kenneth G.

doi:10.1007/978-1-4615-1277-6_3

Cited by 14 publications

(12 citation statements)

References 42 publications

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“…Although the exact mechanism remains unclear, both ions likely stabilize the interaction between the FVa heavy and light chains and are crucial for the FVa cofactor activity . Furthermore, FV undergoes multiple posttranslational modifications including glycosylation, sulfation, and phosphorylation (for a review on posttranslational modifications in blood coagulation proteins see Hansson and Stenflo). The 3D FV protein structure is further mediated by seven intradomain disulfide bridges in the A and C domains …”

Section: The Factor V Protein Structurementioning

confidence: 99%

“…The structural models have been generated in recent years and provide novel insights into the interactive sites in FVa that are involved in the assembly of the prothrombinase and the ternary complexes. Earlier reviews have focused on the general functionality of FV under normal conditions and in disease states; see Kalafatis and Mann and Nicolaes and Dahlbäck…”

Section: Introductionmentioning

confidence: 99%

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Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding

Schreuder

Reitsma

Bos

2019

Journal of Thrombosis and Haemostasis

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Blood coagulation factor Va serves an indispensable role in hemostasis as cofactor for the serine protease factor Xa. In the presence of an anionic phospholipid membrane and calcium ions, factors Va and Xa assemble into the prothrombinase complex. Following formation of the ternary complex with the macromolecular zymogen substrate prothrombin, the latter is rapidly converted into thrombin, the key regulatory enzyme of coagulation. Over the years, multiple binding sites have been identified in factor Va that play a role in the interaction of the cofactor with factor Xa, prothrombin, or the anionic phospholipid membrane surface. In this review, an overview of the currently available information on these interactive sites in factor Va is provided, and data from biochemical approaches and 3D structural protein complex models are discussed. The structural models have been generated in recent years and provide novel insights into the molecular requirements for assembly of both the prothrombinase and the ternary prothrombinase‐prothrombin complexes. Integrated knowledge of functionally important regions in factor Va will allow for a better understanding of factor Va cofactor activity.

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Section: The Factor V Protein Structurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding

Schreuder

Reitsma

Bos

2019

Journal of Thrombosis and Haemostasis

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“…The latter is generated by cleavage of intact FV at R506 by APC and serves as a cofactor for the protein S–dependent inactivation of FVIIIa by APC. APC resistance of FV Leiden thereby enhances the thrombosis risk of heterozygous and homozygous carriers by 4‐ to 6‐fold and by 30‐ to 80‐fold, respectively (reviewed in ). The high allelic frequency of the FV Leiden polymorphism in Caucasians (5–15%), together with genomic features indicating its origin in a single individual ~ 40 000 years ago , has led to suggestions that APC‐resistant FV may have been positively selected during human evolution.…”

Section: Introductionmentioning

confidence: 99%

Survival advantage of heterozygous factor V Leiden carriers in murine sepsis

Kerschen

Hernández

Zogg

et al. 2015

Journal of Thrombosis and Haemostasis

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Summary Background The high allelic frequency of the prothrombotic Leiden polymorphism in human blood coagulation factor V (fV) has been speculated to reflect positive selection during evolution. Heterozygous Leiden carriers enrolled in the placebo arm of the PROWESS sepsis trial, and heterozygous Leiden mice challenged with endotoxin both showed reduced mortality, whereas homozygous Leiden mice were not protected from lethal endotoxemia. Follow-up analyses of clinical outcomes, and of mouse models of infection with various pathogens remained inconclusive. Objective To establish whether aPC-resistance of fV Leiden modifies the outcome of bacterial infection in murine sepsis models. Methods Homozygous and heterozygous fV Leiden mice were subjected to gram-positive (S.aureus) or gram-negative (Y.pestis; E.coli) septic peritonitis, or polymicrobial, focal septic peritonitis induced by cecal ligation and puncture (CLP); and the effect of fV Leiden on 7-day survival and bacterial dissemination was assessed. Outcomes were compared to the sepsis survival of mice with genetically impaired hemostasis (hemophilia A, thrombocytopenia, thrombin receptor PAR4 deficiency, protein C receptor ProcR/EPCR-deficiency). Results Heterozygous, but not homozygous Leiden mice were protected from lethal infection with highly virulent S.aureus and Y.pestis strains. FV Leiden did not affect the outcome of sepsis induced by CLP, staphylokinase-deficient S.aureus, Pla-deficient Y.pestis, or E.coli. Thrombocytopenia, deficiency of PAR1 or PAR4 did not affect S.aureus sepsis survival, whereas hemophilia A increased mortality. ProcR-deficiency selectively abolished the survival advantage of heterozygous Leiden mice. Conclusions In mice, heterozygous fV Leiden carriers are protected from sepsis mortality after infection with clinically relevant human bacterial pathogens.

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“…Thus, it has been demonstrated that amino acid residues 307-348 of fVa provide an interactive site for fXa (18,46) and that selected Lys/Arg residues of the same sequence are susceptible to inactivation cleavage by plasmin in the presence, but not in the absence of PCPS vesicles (47). It is also known that the cleavage at Arg-306 of fVa by activated protein C requires the interaction of the cofactor with anionic phospholipids, further supporting the hypothesis that this region of the cofactor may undergo structural changes upon incorporation into PCPS vesicles (48,49).…”

Section: Discussionmentioning

confidence: 99%

Membrane-Dependent Interaction of Factor Xa and Prothrombin with Factor Va in the Prothrombinase Complex

et al. 2009

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Because all three protein components of prothrombinase, factors (f) Xa and Va and prothrombin, bind to negatively charged membrane phospholipids, the exact role of the membrane in the prothrombinase reaction has not been fully understood. In this study, we prepared deletion derivatives of fXa and prothrombin in which both the Gla and first EGF-like domains of the protease (E2-fXa) as well as the Gla and both kringle domains of the substrate (prethrombin-2) were deleted. The fVamediated catalytic activity of E2-fXa toward prethrombin-2 was analyzed in both the absence and presence of phospholipids composed of 80% phosphatidylcholine (PC) and 20% phosphatidylserine (PS). PCPS markedly accelerated the initial rate of prethrombin-2 activation by E2-fXa, with the cofactor exhibiting saturation only in the presence of phospholipids (apparent K d ∼60 nM). Competitive kinetic studies in the presence of the two exosite-1-specific ligands Tyr 63 -sulfated hirudin [54][55][56][57][58][59][60][61][62][63][64][65] and TM456 suggested that while both peptides are highly effective inhibitors of the fVamediated activation of prethrombin-2 by E2-fXa in the absence of PCPS, they are ineffective competitors in the presence of phospholipids. Since neither E2-fXa nor prethrombin-2 can interact with membranes, these results suggest that fVa interaction with PCPS improves the affinity of the activation complex for the proexosite-1 of the substrate. Direct binding studies employing OG 488 -EGR-labeled fXa and E2-fXa revealed that the interaction of the Gla-domain of fXa with PCPS also induces conformational changes in the protease to facilitate its high-affinity interaction with fVa.Factor X is a vitamin K-dependent serine protease zymogen in plasma that upon activation to factor Xa (fXa) 1 binds with high affinity to other components of the prothrombinase complex (fVa, negatively charged phospholipid vesicles and calcium) in order to activate prothrombin to thrombin during the blood coagulation process (1-5). The complex formation improves the catalytic efficiency of fXa by greater than 5 orders of magnitude by decreasing the apparent K m of prothrombin ∼100-fold and increasing the k cat ∼1000-fold (2,6). The decrease in K m is thought to be due to the γ-carboxyglutamic acid (Gla) dependent interaction of both fXa and prothrombin with negatively charged phospholipid vesicles which raises the local concentration of prothrombin near the enzyme complex, while the increase in k cat is largely attributed to the cofactor effect of fVa in the reaction (7,8). The mechanism by which fVa improves k cat of prothrombin activation by fXa in the prothrombinase complex is poorly understood, though it has been established that several protein-membrane and protein-protein interactions are the driving force behind the high catalytic efficiency of fXa in the prothrombinase complex (8)(9)(10)(11). Thus, a recent study has postulated that fVa binding to fXa in the prothrombinase complex exposes a new binding exosite on the protease that is a recog...

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Factor V: Dr. Jeckyll and Mr. Hyde

Cited by 14 publications

References 42 publications

Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding

Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding

Survival advantage of heterozygous factor V Leiden carriers in murine sepsis

Membrane-Dependent Interaction of Factor Xa and Prothrombin with Factor Va in the Prothrombinase Complex

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