Coagulation factor XIIIa substrates in human plasma: identification and incorporation into the clot.
Coagulation factor XIII (FXIII) is a transglutaminase with a well defined role in the final stages of blood coagulation. Active FXIII (FXIIIa) catalyzes the formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific Gln and Lys residues. The primary physiological outcome of this catalytic activity is stabilization of the fibrin clot during coagulation. The stabilization is achieved through the introduction of cross-links between fibrin monomers and through cross-linking of proteins with anti-fibrinolytic activity to fibrin. FXIIIa additionally cross-links several proteins with other functionalities to the clot. Cross-linking of proteins to the clot is generally believed to modify clot characteristics such as proteolytic susceptibility and hereby affect the outcome of tissue damage. In the present study, we use a proteomic approach in combination with transglutaminase-specific labeling to identify FXIIIa plasma protein substrates and their reactive residues. The results revealed a total of 147 FXIIIa substrates, of which 132 have not previously been described. We confirm that 48 of the FXIIIa substrates were indeed incorporated into the insoluble fibrin clot during the coagulation of plasma. The identified substrates are involved in, among other activities, complement activation, coagulation, inflammatory and immune responses, and extracellular matrix organization.
Department of Molecular Biology and Genetics, Science Park, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark; Interdisciplinary Nanoscience Center, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Camilla Lund
CL
Nikolajsen
Department of Molecular Biology and Genetics, Science Park, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Thomas F
TF
Dyrlund
Department of Molecular Biology and Genetics, Science Park, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark.
Ebbe Toftgaard
ET
Poulsen
Department of Molecular Biology and Genetics, Science Park, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark; Interdisciplinary Nanoscience Center, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark. Electronic address: jje@mb.au.dk.
Jan J
JJ
Enghild
Department of Molecular Biology and Genetics, Science Park, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark. Electronic address: csss@mb.au.dk.
Carsten
C
Scavenius
D001777:Blood Coagulation / Q000502:physiology*; D001798:Blood Proteins / Q000378:metabolism*; D026122:Factor XIIIa / Q000378:metabolism*; D006801:Humans; D020543:Proteome / Q000378:metabolism*; D013379:Substrate Specificity
D001798:Blood Proteins; D020543:Proteome; D026122:Factor XIIIa
Blood Coagulation Factors; Fibrinogenesis; Plasma; Proteomics; Transglutaminases