Factor XIII: novel structural and functional aspects

• Published in: Journal of thrombosis and haemostasis 2011-01, Vol.9 (1), p.9-20
• Main Authors: KOMÁROMI, I., BAGOLY, Z., MUSZBEK, L.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; factor XIII; Factor XIII - chemistry; Factor XIII - metabolism; factor XIII activation; factor XIII structure; Factor XIIIa - metabolism; Fibrinogen - metabolism; Hemostasis; Humans; Models, Molecular; molecular modeling; Molecular Sequence Data; Protein Conformation; Protein Multimerization; Protein Subunits; Structure-Activity Relationship; Substrate Specificity; Thrombin - metabolism; transglutaminase
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2010.04070.x

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.