Factor XIII: novel structural and functional aspects

Authors

  • I. KOMÁROMI,

    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
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  • Z. BAGOLY,

    1. Clinical Research Center
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  • L. 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
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László Muszbek, University of Debrecen, Medical and Health Science Center, Clinical Research Center, POBox 40, H-4012 Debrecen, Hungary.
Tel.: +36 52431956; fax: +36 52340011.
E-mail: muszbek@med.unideb.hu

Abstract

Summary.  Factor (F)XIII is a protransglutaminase that, in addition to maintaining hemostasis, has multiple plasmatic and intracellular functions. Its plasmatic form (pFXIII) is a tetramer of two potentially active A (FXIII-A) and two inhibitory/carrier B (FXIII-B) subunits, whereas its cellular form (cFXIII) is a dimer of FXIII-A. FXIII-A belongs to the family of transglutaminases (TGs), which show modest similarity in the primary structure, but a high degree of conservatism in their domain and sub-domain secondary structure. FXIII-A consists of an activation peptide, a β-sandwich, a catalytic and two β-barrel domains. FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds. The structural elements of FXIII-A involved in the interaction with FXIII-B have not been elucidated; in FXIII-B the first sushi domain seems important for complex formation. In the circulation pFXIII is bound to the fibrinogen γ’-chain through its B subunit. In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca2+ FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen). cFXIII does not require proteolysis for intracellular activation. The three-dimensional structure of FXIIIa has not been resolved. Based on analogies with transglutaminase-2, a three-dimensional structure of FXIIIa was developed by molecular modeling, which shows good agreement with the drastic structural changes demonstrated by biochemical studies. The structural requirements for enzyme-substrate interaction and for transglutaminase activity are also reviewed.

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