The dimeric structure of factor XI and zymogen activation

Blood. 2013 May 9;121(19):3962-9. doi: 10.1182/blood-2012-12-473629. Epub 2013 Mar 20.

Abstract

Factor XI (fXI) is a homodimeric zymogen that is converted to a protease with 1 (1/2-fXIa) or 2 (fXIa) active subunits by factor XIIa (fXIIa) or thrombin. It has been proposed that the dimeric structure is required for normal fXI activation. Consistent with this premise, fXI monomers do not reconstitute fXI-deficient mice in a fXIIa-dependent thrombosis model. FXI activation by fXIIa or thrombin is a slow reaction that can be accelerated by polyanions. Phosphate polymers released from platelets (poly-P) can enhance fXI activation by thrombin and promote fXI autoactivation. Poly-P increased initial rates of fXI activation 30- and 3000-fold for fXIIa and thrombin, respectively. FXI monomers were activated more slowly than dimers by fXIIa in the presence of poly-P. However, this defect was not observed when thrombin was the activating protease, nor during fXI autoactivation. The data suggest that fXIIa and thrombin activate fXI by different mechanisms. FXIIa may activate fXI through a trans-activation mechanism in which the protease binds to 1 subunit of the dimer, while activating the other subunit. For activation by thrombin, or during autoactivation, the data support a cis-activation mechanism in which the activating protease binds to and activates the same fXI subunit.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carotid Artery Thrombosis / genetics
  • Carotid Artery Thrombosis / metabolism
  • Factor XI / chemistry*
  • Factor XI / genetics
  • Factor XI / metabolism*
  • Factor XI Deficiency / genetics
  • Factor XI Deficiency / metabolism
  • Factor XIIa / chemistry
  • Factor XIIa / metabolism
  • Factor XIa / chemistry
  • Factor XIa / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Quaternary

Substances

  • Factor XI
  • Factor XIa
  • Factor XIIa