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The hydrophobic residues at the amino terminus of the gamma-carboxyglutamic acid-rich region of human protein C are required for phospholipid (PL) binding and other PL-based activities. Leusine residues at positions 5 and 8 are important, as substitutions in these residues bring about changes in binding activity and are probably required for correct orientation of the enzymes on the PL surface. Human protein C belongs to a family of blood coagulation proteins that require vitamin K for activity.

The functional properties of individual gamma-carboxyglutamic acid (Gla) residues of human protein C (PC) and activated protein C (APC) are studied using site-directed mutagenesis. Ca2+- and phospholipid-dependent anticoagulant properties of PC and APC do not require Gla14 and Gla19. Ca2+ coordination is facilitated by a single carboxylate of the Gla6 residue which is a crucial Ca2+ binding site.

The properties of gamma-carboxyglutamic acid (Gla) containing activated protein C and chimeric human protein C are studied by substituting helical stack (HS) domains of protein C with human coagulation factor IX. Gla and HS domains of the proteins are influenced by calcium ions, with homologous properties detected in factor IX. The calcium sites located outside protein domains is independent of the native Gla/HC domains within the protein.