Restoring the Procofactor State of Factor Va-like Variants by Complementation with B-domain Peptides

Bunce, Matthew W.; Bos, Mettine H.A.; Krishnaswamy, Sriram; Camire, Rodney M.

doi:10.1074/jbc.m113.506840

Cited by 27 publications

(60 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This acidic region of the B domain interacts with a basic region, also within the B domain, to maintain FV in an inactive, procofactor conformation. [127][128][129] These regions appear to function by preventing FXa from binding to the FV heavy chain, and removal of either the acidic or basic region is sufficient to relieve this inhibition and convert FV into FVa. 127,128 Interestingly, the FV B-domain basic region contains an amino acid sequence almost identical to one found within the C terminus of TFPIa.…”

Section: Inhibition Of Prothrombinase By Tfpiamentioning

confidence: 99%

“…[127][128][129] These regions appear to function by preventing FXa from binding to the FV heavy chain, and removal of either the acidic or basic region is sufficient to relieve this inhibition and convert FV into FVa. 127,128 Interestingly, the FV B-domain basic region contains an amino acid sequence almost identical to one found within the C terminus of TFPIa. This sequence is highly conserved in both proteins across mammalian species, suggesting that it performs an important physiological function (Figure 4).…”

Section: Inhibition Of Prothrombinase By Tfpiamentioning

confidence: 99%

See 1 more Smart Citation

Biology of tissue factor pathway inhibitor

Wood

Ellery

Maroney

et al. 2014

Blood

239

249

View full text Add to dashboard Cite

Recent studies of the anticoagulant activities of the tissue factor (TF) pathway inhibitor (TFPI) isoforms, TFPIα and TFPIβ, have provided new insight into the biochemical and physiological mechanisms that underlie bleeding and clotting disorders. TFPIα and TFPIβ have tissue-specific expression patterns and anticoagulant activities. An alternative splicing event in the 5′ untranslated region allows for translational regulation of TFPIβ expression. TFPIα has 3 Kunitz-type inhibitor domains (K1, K2, K3) and a basic C terminus, whereas TFPIβ has the K1 and K2 domains attached to a glycosylphosphatidyl inositol–anchored C terminus. TFPIα is the only isoform present in platelets, whereas endothelial cells produce both isoforms, secreting TFPIα and expressing TFPIβ on the cell surface. TFPIα and TFPIβ inhibit both TF–factor VIIa–dependent factor Xa (FXa) generation and free FXa. Protein S enhances FXa inhibition by TFPIα. TFPIα produces isoform-specific inhibition of prothrombinase during the initiation of coagulation, an anticoagulant activity that requires an exosite interaction between its basic C terminus and an acidic region in the factor Va B domain. Platelet TFPIα may be optimally localized to dampen initial thrombin generation. Similarly, endothelial TFPIβ may be optimally localized to inhibit processes that occur when endothelial TF is present, such as during the inflammatory response.

show abstract

Section: Inhibition Of Prothrombinase By Tfpiamentioning

confidence: 99%

Section: Inhibition Of Prothrombinase By Tfpiamentioning

confidence: 99%

Biology of tissue factor pathway inhibitor

Wood

Ellery

Maroney

et al. 2014

Blood

239

249

View full text Add to dashboard Cite

show abstract

“…The BR and the AR interact with each other and maintain FV in its inactive state (52,53). Removal of either the BR or the AR results in a constitutively active FVa molecule, and removal of both regions yields the fully active FVa molecule (52,53). Further, similar to the BR of FV, the C-terminal regions of TFPI-1 and TFPI-2 contain several Arg and Lys residues (1)(2)(3).…”

mentioning

confidence: 99%

“…The B-domain contains two highly conserved sequences, termed the basic region (BR, residues 963-1008) and the acidic region (AR, residues 1493-1537). The BR and the AR interact with each other and maintain FV in its inactive state (52,53). Removal of either the BR or the AR results in a constitutively active FVa molecule, and removal of both regions yields the fully active FVa molecule (52,53).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Platelets Contain Tissue Factor Pathway Inhibitor-2 Derived from Megakaryocytes and Inhibits Fibrinolysis

Vadivel

Ponnuraj

Kumar

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: TFPI-2 inhibits plasma kallikrein, FXIa, and plasmin, but its concentration in normal plasma is insufficient to inhibit clotting or fibrinolysis. Results: Platelets contain TFPI-2 derived from megakaryocytes and binds to platelet FV/Va and circulating FV in late pregnancy when plasma TFPI-2 is ϳ7 nM. Conclusion: Platelet-derived TFPI-2 regulates intrinsic coagulation and tPA-induced fibrinolysis. Significance: Platelet-derived TFPI-2 promotes clot stabilization while attenuating intrinsic clotting.

show abstract

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Dahlbäck

Guo

Livaja-Koshiar

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

Essentials FV‐Short, a normal splice isoform of Factor V, binds tissue factor pathway inhibitor (TFPIα) with high affinity.FV‐Short functions as a synergistic TFPIα cofactor with protein S in inhibition of Factor Xa.FV‐Short is much more efficient as TFPIα cofactor than full length FV.TFPIα‐cofactor activity of FV‐Short is lost upon activation of coagulation by thrombin‐mediated cleavage. Background FV‐Short is a normal splice variant of Factor V (FV) having a short B domain, which exposes a high affinity‐binding site for tissue factor pathway inhibitor α (TFPIα). FV‐Short and TFPIα circulate in complex in plasma.ObjectivesThe aim was to elucidate whether FV‐Short affects TFPIα as inhibitor of coagulation FXa and to test whether the TFPIα‐cofactor activity of protein S is influenced by FV‐Short.MethodsRecombinant FV, wild‐type FV‐Short and a FV‐Short thrombin‐cleavage resistant variant were expressed and purified. The influence of FV and FV‐Short variants and/or protein S on the FXa inhibitory activity of TFPIα was monitored both in a purified system and in a plasma‐based thrombin generation assay.Results FV‐Short had intrinsically weak TFPIα‐cofactor activity but with protein S present, FV‐Short yielded efficient inactivation of FXa. Protein S alone did not promote full TFPIα‐activity. Intact FV was inefficient at low protein S concentrations and had 10‐fold lower activity compared to FV‐Short at physiological protein S levels. Activation of FV‐Short by thrombin resulted in the loss of the TFPIα‐cofactor activity. The synergistic TFPIα‐cofactor activity of FV‐Short and protein S was also demonstrated in plasma using a thrombin generation assay.Conclusions FV‐Short and protein S are highly efficient, synergistic cofactors to TFPIα in the regulation of FXa activity, whereas full length FV has lower activity. Our results suggest the formation of an efficient FXa‐inhibitory complex between FV‐Short, TFPIα and protein S on the surface of negatively charged phospholipids.

show abstract

Restoring the Procofactor State of Factor Va-like Variants by Complementation with B-domain Peptides

Cited by 27 publications

References 68 publications

Biology of tissue factor pathway inhibitor

Biology of tissue factor pathway inhibitor

Platelets Contain Tissue Factor Pathway Inhibitor-2 Derived from Megakaryocytes and Inhibits Fibrinolysis

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Contact Info

Product

Resources

About