Factor VII and protein C are phosphatidic acid-binding proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Hematology

Background:

• Seven proteins in the human blood clotting cascade utilize their GLA domains for membrane binding.
• Binding affinity to phosphatidylserine (PS)-containing membranes varies significantly among these proteins.

Purpose of the Study:

• To quantify the phospholipid binding specificities of seven human blood clotting proteins.
• To investigate the role of different phospholipid headgroups in protein binding and enzymatic activity.

Main Methods:

• Utilized nanodiscs of defined phospholipid composition to measure protein-membrane interactions.
• Employed liposomes to assess the impact of phospholipids on proteolytic activity.
• Investigated the effect of phospholipase D treatment on activated human platelets.

Main Results:

• All seven proteins showed preferential binding to PS with l-serine over d-serine headgroups.
• Factor VIIa and activated protein C bound significantly more to phosphatidic acid (PA) than PS.
• PA-containing liposomes enhanced factor VIIa and activated protein C proteolytic activity.
• Phosphatidylinositol 4-phosphate also supported enhanced enzymatic activity.

Conclusions:

• Factor VIIa and activated protein C preferentially bind to monoester phosphates found in PA and phosphatidylinositol 4-phosphate.
• This preference is attributed to the accessibility and higher negative charge of monoester phosphates.
• Findings suggest implications for the in vivo function of these proteases in the blood clotting cascade.