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Thromb Haemost 2008; 99(04): 668-674
DOI: 10.1160/TH07-09-0577
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Cleavage of factor XIII by human neutrophil elastase results in a novel active truncated form of factor XIII A subunit

Zsuzsa Bagoly
1   Clinical Research Center
2   Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
Ferenc Fazakas
2   Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
István Komáromi
2   Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
Gizella Haramura
1   Clinical Research Center
,
Eszter Tóth
2   Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
László Muszbek
1   Clinical Research Center
2   Thrombosis, Haemostasis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
› InstitutsangabenFinancial support: This work was supported by grants from the Hungarian National Research Fund (OTKA-NKTH NI 69238), from the Hungarian Academy of Sciences (MTA 2006TKI227), from the Hungarian Ministry of Health and Social Affairs (ETT 406/2006) and from the National Office of Research and Technology (NKTH RET-06/2004).
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Publikationsverlauf

Received: 24. September 2007

Accepted after major revision: 19. Februar 2008

Publikationsdatum:
25. November 2017 (online)

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Summary

The first step in the activation of plasma factor XIII (FXIII) is the cleavage of R37-G38 bond in FXIIIA subunit (FXIII-A) by thrombin, which makes the subsequent formation of an active transglutaminase possible. No active truncated form of FXIII-A, other than G38-FXIII-A, has been identified. In contrast to thrombin, which has a preference toward arginine residues, human neutrophil elastase (HNE) cleaves peptide bonds at small side-chain aliphatic amino acids, preferably at valine. As there are several valine residues close to the thrombin cleavage-site, we tested if an active truncated FXIII-A was formed during fragmentation of FXIII by HNE. It was demonstrated by Western blotting and transglutaminase assay that HNE induced a limited cleavage of FXIII-A resulting in the activation of both plasma and cellular FXIII; the maximal transglutaminase activities were 52.5% and 67.4% of thrombin-activated FXIII, respectively. After the relatively rapid activation a much slower inactivation occurred. HNE-activated FXIII cross-linked fibrin γ- and α-chains in the clot formed by batroxobin moojeni. MALDI-TOF analysis of the cleaved fragments and N-terminal Edman degradation of the truncated protein identified V39-N40 as the primary cleavagesite and N40-FXIII-A as the active form. No primary cleavage occurred at V34, V35, V47, V50 residues. FXIII-A V34L polymorphism, which increases the rate of FXIII-A cleavage by thrombin, was without effect on FXIII activation by HNE. Molecular modeling located the primary HNE cleavage-site in the middle of the flexible and accessible Q32-L45 loop and showed that other neighboring valine residues were in less favorable position.

Keywords

Factor XIII - transglutaminase - elastase - factor XIII-A V34L polymorphism
 

  • References

  • 1 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: structure and function. Thromb Res 1999; 94: 271-305.
    CrossrefPubMedGoogle Scholar
  • 2 Greenberg CS, Sane DC, Lai T. Factor XIII and fibrin stabilization. Hemostasis and Thrombosis. 5th edn. Philadelphia: Lippincott Williams and Wilkins; 2006: 153-181.
    Google Scholar
  • 3 Wartiovaara U, Mikkola H, Szôke G. et al. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A. Thromb Haemost 2000; 84: 595-600.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 4 Ariens RA, Philippou H, Nagaswami C. et al. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96: 988-995.
    PubMedGoogle Scholar
  • 5 Balogh I, Szôke G, Kárpáti L. et al. Val34Leu polymorphism of plasma FXIII: biochemistry and epidemiology in familial thrombophilia. Blood 2000; 96: 2479-2486.
    PubMedGoogle Scholar
  • 6 Walter M, Nyman D, Krajnc V. et al. The activation of plasma factor XIII with the snake venom enzymes ancrod and batroxobin marajoensis. Thromb Haemost 1977; 38: 438-446.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 7 Niewiarowski S, Kirby EP, Brudzynski TM. et al. Thrombocytin, a serine protease from Bothrops atrox venom. 2. Interaction with platelets and plasma-clotting factors. Biochemistry 1979; 18: 3570-3577.
    CrossrefPubMedGoogle Scholar
  • 8 Kopec M, Latallo ZS, Stahl M. et al. The effect of proteolytic enzymes on fibrin stabilizing factor. Biochim Biophys Acta 1969; 181: 437-445.
    CrossrefPubMedGoogle Scholar
  • 9 Schwartz ML, Pizzo SV, Hill RL. et al. Human factor XIII from plasma and platelets. Molecular weights, subunit structures, proteolytic activation, and crosslinking of fibrinogen and fibrin. J Biol Chem 1973; 248: 1395-1407.
    PubMedGoogle Scholar
  • 10 McDonagh J, McDonagh RP. Alternative pathways for the activation of factor XIII. Br J Haematol 1975; 30: 465-477.
    CrossrefPubMedGoogle Scholar
  • 11 Dall’Acqua W, Halin C, Rodrigues ML. et al. Elastase substrate specificity tailored through substrate-assisted catalysis and phage display. Protein Eng 1999; 12: 981-987.
    CrossrefPubMedGoogle Scholar
  • 12 Harris JL, Backes BJ, Leonetti F. et al. Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries. Proc Natl Acad Sci USA 2000; 97: 7754-7759.
    CrossrefPubMedGoogle Scholar
  • 13 Koehl C, Knight CG, Bieth JG. Compared action of neutrophil proteinase 3 and elastase on model substrates. J Biol Chem 2003; 278: 12609-12612.
    CrossrefPubMedGoogle Scholar
  • 14 Kawabata K, Suzuki M, Sugitani M. et al. ONO-5046, a novel inhibitor of human neutrophil elastase. Biochem Biophys Res Commun 1991; 177: 814-820.
    CrossrefPubMedGoogle Scholar
  • 15 Lorand L, Credo RB, Janus TG. Factor XIII (fibrin stabilizing factor). Methods Enzymol 1981; 80: 333-341.
    PubMedGoogle Scholar
  • 16 Polgár J, Hidasi V, Muszbek L. Non-proteolytic activation of cellular protransglutaminase (placental macrophage factor XIII). Biochem J 1990; 267: 557-560.
    CrossrefPubMedGoogle Scholar
  • 17 Shemirani AH, Muszbek L. Rapid detection of the factor XIII Val34Leu (163 G–>T) polymorphism by real-time PCR using fluorescence resonance energy transfer detection and melting curve analysis. Clin Chem Lab Med 2004; 42: 877-879.
    PubMedGoogle Scholar
  • 18 Kárpáti L, Penke B, Katona E. et al. A modified, optimized kinetic photometric assay for the determination of blood coagulation factor XIII activity in plasma. Clin Chem 2000; 46: 1946-1955.
    PubMedGoogle Scholar
  • 19 Siebenlist KR, Meh DA, Mosesson MW. Protransglutaminase (Factor XIII) mediated crosslinking of fibrinogen and fibrin. Thromb Haemost 2001; 86: 1221-1228.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 20 Hunkapiller MW, Hewick RM, Dreyer WJ, Hood LE. High-sensitivity sequencing with a gas-phase sequenator. Methods Enzymol 1983; 91: 399-413.
    PubMedGoogle Scholar
  • 21 Weiss MS, Metzner HJ, Hilgenfeld R. Two non-proline cis peptide bonds may be important for factor XIII function. FEBS Letters 1998; 423: 291-296.
    CrossrefPubMedGoogle Scholar
  • 22 Humphrey W, Dalke A, Schulten K. VMD – Visual Molecular Dynamics. J Molec Graphics 1996; 14: 33-38.
    CrossrefPubMedGoogle Scholar
  • 23 Hornyak TJ, Shaffer JA. Role of calcium ion in the generation of factor XIII activity. Biochemistry 1991; 30: 6175-6182.
    CrossrefPubMedGoogle Scholar
  • 24 Stocker K. Application of snake venom proteins in the diagnosis of hemostatic disorders. Stocker K. Medical use of snake venom proteins.. Boca Raton: CRC-Press; 1990: 213-252.
    Google Scholar
  • 25 Holleman WH, Weiss LJ. The thrombin-like enzyme from Bothrops atrox snake venom. J Biol Chem 1976; 251: 1663-1669.
    PubMedGoogle Scholar
  • 26 Schmidt W, Egbring R, Havemann K. Effect of elastase-like and chymotrpysin-like neutral proteases from human granulocytes on isolated clotting factors. Thromb Res 1975; 5: 315-326.
    PubMedGoogle Scholar
  • 27 Klingemann HG, Egbring R, Holst F. et al. Degradation of human plasma fibrin stabilizing factor XIII subunits by human granulocytic proteinases. Thromb Res 1982; 25: 793-801.
    PubMedGoogle Scholar
  • 28 Henriksson P, Nilsson IM, Ohlsson K. et al. Granulocyte elastase activation and degradation of factor XIII. Thromb Res 1980; 18: 343-351.
    CrossrefPubMedGoogle Scholar
  • 29 Radek JT, Jeong JM, Wilson J. et al. Association of A subunits of recombinant placental factor XIII with the native carrier B subunits from human plasma. Biochemistry 1993; 32: 3527-3534.
    CrossrefPubMedGoogle Scholar
  • 30 Lorand L, Jeong JM, Radek JT. et al. Human plasma factor XIII: Subunit interactions and activation of zymogen. Methods Enzymol 1993; 222: 22-35.
    PubMedGoogle Scholar
  • 31 Yee VC, Pedersen LC, Bishop PD. et al. Structural evidence that the activation peptide is not released upon thrombin cleavage of factor XIII. Thromb Res 1995; 78: 389-397.
    CrossrefPubMedGoogle Scholar
  • 32 Schroeder V, Vuissoz J, Caflisch A. et al. Factor XIII activation peptide is released into plasma upon cleavage by thrombin and shows a different structure compared to its bound form. Thromb Haemost 2007; 97: 890-898.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 33 Samis JA, Garrett M, Manuel RP. et al. Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V. Blood 1997; 90: 1065-1074.
    PubMedGoogle Scholar
  • 34 Machovich R, Owen WG. The elastase-mediated pathway of fibrinolysis. Blood Coag Fibrinol 1990; 1: 79-90.
    CrossrefPubMedGoogle Scholar
  • 35 Katona É, Haramura G, Kárpáti L. et al. A simple, quick one-step ELISA assay for the determination of complex plasma factor XIII (A2B2). Thromb Haemost 2000; 83: 268-273.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 36 Wiedow O, Muehle K, Sreit V. et al. Human eosinophils lack human leukocyte elastase. Biochim Biophys Acta 1996; 1315: 185-187.
    CrossrefPubMedGoogle Scholar
  • 37 Falanga A, Marchetti M, Evangelista V. et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96: 4261-4266.
    PubMedGoogle Scholar
  • 38 Wiedow O, Meyer-Hoffert U. Neutrophil serine proteases: potential key regulators of cell signalling during inflammation. J Int Med 2005; 257: 319-328.
    CrossrefPubMedGoogle Scholar
  • 39 Abrams WR, Diamond LW, Kane AB. A flow cytometric assay of neutrophil degranulation. J Histochem Cytochem 1983; 31: 737-744.
    CrossrefPubMedGoogle Scholar
  • 40 Achyuthan KE. Characterization of the reciprocal binding sites on human α-thrombin and factor XIII A-chain. Mol Cel Biochem 1998; 178: 289-297.
    CrossrefPubMedGoogle Scholar
  • 41 Bagoly Z, Haramura G, Muszbek L. Down-regulation of activated factor XIII by polymorphonuclear granulocyte proteases within fibrin clot. Thromb Haemost 2007; 98: 359-367.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 42 Spencer LT, Paone G, Krein PM. et al. Role of human neutrophil peptides in lung inflammation associated with α1-antitrypsin deficiency. Am J Physiol Lung Cell Mol Physiol 2004; 286: L514-520.
    CrossrefPubMedGoogle Scholar
  • 43 Katona É, Nagy B, Kappelmayer J. et al. Factor XIII in bronchoalveolar lavage fluid from children with chronic bronchoalveolar inflammation. J Throm Haemost 2005; 3: 1407-1413.
    CrossrefPubMedGoogle Scholar