Crystal structure of coagulation factor XII N-terminal domains 1-5

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Medicine

Background:

• Factor XIIa (FXIIa) initiates inflammatory and coagulation cascades.
• FXIIa is activated by polyanions, with its N-terminal domains mediating ligand binding.
• Understanding FXII N-terminal domain structure is key to its function.

Purpose of the Study:

• To elucidate the structural basis of polyanion and Zn2+ coordination in Factor XII N-terminal domains.
• To determine the three-dimensional arrangement of FXII N-terminal domains and their ligand-binding sites.

Main Methods:

• X-ray crystallography of recombinant FXII domains (FXII^HC5) and isolated FnII domain.
• Native mass spectrometry, small-angle X-ray scattering, and gel-filtration chromatography.

Main Results:

• Crystal structures revealed domain interactions, including head-to-tail FnII-kringle interactions and monomer interlocking.
• FXII^HC5 monomers and dimers were observed in solution, with specific domain arrangements.
• Identified coordinated binding sites for polyanions and Zn2+ across multiple domains.

Conclusions:

• The mosaic domain structure of FXII N-terminus assembles diverse ligand-binding sites in a unique 3D framework.
• These findings provide a structural basis for FXII activation mechanisms.
• Offers insights into potential therapeutic targets for FXII-mediated diseases.