Factor XII truncation accelerates activation in solution.

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• The contact activation system and innate immune system are interconnected in inflammatory processes.
• Plasma kallikrein (PKa) processes factor XII (FXII), first activating it and then truncating it.
• Truncation of FXII removes surface-binding domains, a process that negatively regulates coagulation.

Purpose of the Study:

• To investigate how FXII truncation influences its activation.
• To examine the impact of truncation on downstream kallikrein-kinin system activation.

Main Methods:

• Activation of recombinant FXII variants was studied using chromogenic assays.
• FXIIa levels were quantified via ELISA and western blotting.

Main Results:

• FXII truncation was shown to prime FXII for activation by PKa in solution.
• Truncation at the R334 site accelerated FXIIa formation, with the FXII-R334A mutant showing 50% reduced activity.
• A pathogenic mutation causing hereditary angioedema synergistically accelerated FXII activation.
• New cleavage sites in FXII, including those sensitive to neutrophil elastase and cathepsin K, were identified, priming FXII for PKa activation.

Conclusions:

• FXII truncation, whether from pathogenic mutations or natural cleavage sites, primes FXII for activation in solution.
• The surface-binding domains of FXII may shield its activating cleavage site (R353).
• This mechanism could explain the contact system's role in inflammatory pathology.