The Val34Leu Polymorphism in the A Subunit of Coagulation Factor XIII Contributes to the Large Normal Range in Activity and Demonstrates That the Activation Peptide Plays a Role in Catalytic Activity

There is a wide normal range of coagulation factor XIII activity that has never been adequately explained. A polymorphism substituting leucine for valine at position 34 in the activation peptide of the A subunit of factor XIII has recently been discovered in nondeficient individuals, and the present studies indicate that the leucine substitution results in a significant increase in transglutaminase activity. The frequency of the Leu34 allele in the Australian Caucasian population is 0.27, which is high enough to suggest that the inheritance of either the Val34 or Leu34 alleles may contribute to the wide normal range of activity. Although there has been structural evidence indicating that the activation peptide does not dissociate from the enzyme after thrombin cleavage, the discovery of elevated activity resulting from the Leu34 substitution is the first direct evidence that the activation peptide plays a continuing role in the function of factor XIII. © 1998 by The American Society of Hematology.

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The Val34Leu Polymorphism in the A Subunit of Coagulation Factor XIII Contributes to the Large Normal Range in Activity and Demonstrates That the Activation Peptide Plays a Role in Catalytic Activity

Blood ◽

10.1182/blood.v92.8.2766 ◽

1998 ◽

Vol 92 (8) ◽

pp. 2766-2770 ◽

Cited By ~ 77

Author(s):

S. Kangsadalampai ◽

P.G. Board

Keyword(s):

Factor Xiii ◽

Direct Evidence ◽

Coagulation Factor ◽

Normal Range ◽

Thrombin Cleavage ◽

Coagulation Factor Xiii ◽

A Subunit ◽

Elevated Activity ◽

Activation Peptide ◽

American Society

Abstract There is a wide normal range of coagulation factor XIII activity that has never been adequately explained. A polymorphism substituting leucine for valine at position 34 in the activation peptide of the A subunit of factor XIII has recently been discovered in nondeficient individuals, and the present studies indicate that the leucine substitution results in a significant increase in transglutaminase activity. The frequency of the Leu34 allele in the Australian Caucasian population is 0.27, which is high enough to suggest that the inheritance of either the Val34 or Leu34 alleles may contribute to the wide normal range of activity. Although there has been structural evidence indicating that the activation peptide does not dissociate from the enzyme after thrombin cleavage, the discovery of elevated activity resulting from the Leu34 substitution is the first direct evidence that the activation peptide plays a continuing role in the function of factor XIII. © 1998 by The American Society of Hematology.

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Expression of Functional Coagulation Factor XIII in Escherichia coli

Thrombosis and Haemostasis ◽

10.1055/s-0038-1645201 ◽

1990 ◽

Vol 63 (02) ◽

pp. 235-240 ◽

Cited By ~ 16

Author(s):

P G Board ◽

K Pierce ◽

M Coggan

Keyword(s):

Escherichia Coli ◽

Factor Xiii ◽

Blood Clotting ◽

Coagulation Factor ◽

E Coli ◽

Thrombin Cleavage ◽

Coagulation Factor Xiii ◽

Clotting Cascade ◽

Tac Promoter ◽

A Subunit

SummaryCoagulation factor XIII is a zymogen that can be activated by thrombin cleavage to a transglutaminase that catalyses the formation of covalent crosslinks between fibrin chains in the final stages of the blood clotting cascade. Although circulating factor-XIII is composed of A and B subunits the catalytic activity is a property of the A subunits. In this study we have constructed a plasmid (pKKF13A) that contains a cDNA encoding the A subunit positioned downstream of a tac promoter. Escherichia coli containing this plasmid produce A subunit protein when grown in the presence of IPTG. The cloned A subunit has been partially purified and characterized. Comparison with A subunits purified from plasma showed that the cloned A subunits were of the same size, assembled as dimers, and had the same native electrophoretic mobility. The cloned A subunits expressed transglutaminase activity with putrescine, dansylcadaverine and casein as substrates, and were able to crosslink fibrin in clots formed from A subunit deficient plasma. These studies have demonstrated that functional recombinant factor XIII A subunit can be produced in E. coli and suggest that recombinant factor XIII can potentially provide a safe and inexhaustible supply for therapeutic use.

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Coagulation factor XIII-A subunit and activation peptide levels in individuals with established symptomatic acute deep vein thrombosis

Thrombosis Research ◽

10.1016/j.thromres.2017.10.009 ◽

2017 ◽

Vol 159 ◽

pp. 96-99 ◽

Cited By ~ 1

Author(s):

Remi O. Kool ◽

Hans P. Kohler ◽

Jonathan M. Coutinho ◽

Marcel Levi ◽

Michiel Coppens ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Factor Xiii ◽

Coagulation Factor ◽

Vein Thrombosis ◽

Coagulation Factor Xiii ◽

A Subunit ◽

Acute Deep Vein Thrombosis ◽

Activation Peptide ◽

Deep Vein

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Coagulation factor XIII variants with altered thrombin activation rates

Biological Chemistry ◽

10.1515/bc.2009.142 ◽

2009 ◽

Vol 390 (12) ◽

Cited By ~ 7

Author(s):

Mette Dahl Andersen ◽

Marianne Kjalke ◽

Susanne Bang ◽

Inger Lautrup-Larsen ◽

Peter Becker ◽

...

Keyword(s):

Factor Xiii ◽

Coagulation Factor ◽

Thrombin Cleavage ◽

Coagulation Factor Xiii ◽

Activation Rate ◽

Fibrin Network ◽

Thrombin Activation ◽

Activation Peptide ◽

Activation Rates ◽

Fibrin Monomers

Abstract Coagulation factor XIII (FXIII) is activated by thrombin and catalyses crosslinking between fibrin monomers thereby providing mechanical strength to the fibrin network. V34L is a common FXIII-A polymorphism found in the activation peptide. FXIII-A V34L is activated faster by thrombin and provides formation of a tighter clot at fibrinogen concentrations in the low end of the physiological range. FXIII-A variants with potentially increased activation rates were generated. Introduction of an optimal thrombin cleavage site, V34L+V35T, increased the activation rate 7.6-fold and facilitated the formation of a fibrin network more resistant to fibrinolysis than obtained with wt FXIII-A. In contrast, introduction of fragments of fibrinopeptide A into the activation peptide resulted in severely impaired activation rates.

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The gene for coagulation factor XIII a subunit (F13A) is distal to HLA on chromosome 6

Human Genetics ◽

10.1007/bf00291400 ◽

1984 ◽

Vol 67 (4) ◽

pp. 406-408 ◽

Cited By ~ 18

Author(s):

P. G. Board ◽

M. Reid ◽

S. Serjeantson

Keyword(s):

Factor Xiii ◽

Coagulation Factor ◽

Chromosome 6 ◽

Coagulation Factor Xiii ◽

A Subunit

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Identification of Potential Novel Interacting Partners for Coagulation Factor XIII B (FXIII-B) Subunit, a Protein Associated with a Rare Bleeding Disorder

International Journal of Molecular Sciences ◽

10.3390/ijms20112682 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2682 ◽

Cited By ~ 3

Author(s):

Sneha Singh ◽

Mohammad Suhail Akhter ◽

Johannes Dodt ◽

Peter Volkers ◽

Andreas Reuter ◽

...

Keyword(s):

Factor Xiii ◽

Regulatory Protein ◽

Coagulation Factor ◽

Factor H ◽

Complement C3 ◽

Complement Factor ◽

B Subunit ◽

Coagulation Factor Xiii ◽

A Subunit ◽

Complement C1q

Coagulation factor XIII (FXIII) is a plasma-circulating heterotetrameric pro-transglutaminase complex that is composed of two catalytic FXIII-A and two protective/regulatory FXIII-B subunits. FXIII acts by forming covalent cross-links within a preformed fibrin clots to prevent its premature fibrinolysis. The FXIII-A subunit is known to have pleiotropic roles outside coagulation, but the FXIII-B subunit is a relatively unexplored entity, both structurally as well as functionally. Its discovered roles so far are limited to that of the carrier/regulatory protein of its partner FXIII-A subunit. In the present study, we have explored the co-presence of protein excipients in commercial FXIII plasma concentrate FibrogamminP by combination of protein purification and mass spectrometry-based verification. Complement factor H was one of the co-excipients observed in this analysis. This was followed by performing pull down assays from plasma in order to detect the putative novel interacting partners for the FXIII-B subunit. Complement system proteins, like complement C3 and complement C1q, were amongst the proteins that were pulled down. The only protein that was observed in both experimental set ups was alpha-2-macroglobulin, which might therefore be a putative interacting partner of the FXIII/FXIII-B subunit. Future functional investigations will be needed to understand the physiological significance of this association.

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Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia

Blood ◽

10.1182/blood.v96.7.2479 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2479-2486 ◽

Cited By ~ 87

Author(s):

István Balogh ◽

Gabriella Szôke ◽

Levente Kárpáti ◽

Ulla Wartiovaara ◽

Éva Katona ◽

...

Keyword(s):

Protective Effect ◽

Venous Thrombosis ◽

Factor Xiii ◽

Coagulation Factor ◽

Wild Type ◽

Thrombin Cleavage ◽

Plasma Factor ◽

Thrombin Activation ◽

A Subunit ◽

The Mean

Abstract Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protective effect against occlusive arterial diseases and venous thrombosis; however, its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concentration of FXIII of different Val34Leu genotypes are identical, which suggests that there is no difference in the rate of synthesis and externalization of wild-type and mutant FXIII-A. In contrast, the release of AP by thrombin from the Leu34 allele proceeded significantly faster than from its wild-type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombin than between the Val34 variant and thrombin. In agreement with these findings, the activation of mutant plasma FXIII by thrombin was faster and required less thrombin than that of the wild-type variant. Full thrombin activation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly, the mean specific FXIII activity in the plasma was the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allele hardly could be associated with its presumed protective effect against venous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia.

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