The SHBG‐like region of protein S is crucial for factor V‐dependent APC‐cofactor function

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Abstract
Activated protein C (APC) regulates blood coagulation by degrading factor Va (FVa) and factor VIIIa (FVIIIa). Protein S is a cofactor to APC in the FVa degradation, whereas FVIIIa degradation is potentiated by the synergistic APC‐cofactor activity of protein S and factor V (FV). To elucidate the importance of the sex‐hormone‐binding globulin (SHBG)‐like region in protein S for expression of anticoagulant activity, a recombinant protein S/Gas6 chimera was constructed. It comprised the amino‐terminal half of protein S and the SHBG‐like region of Gas6, a structurally similar protein having no known anticoagulant properties. The protein S/Gas6 chimera expressed 40–50% APC‐cofactor activity in plasma as compared to wild‐type protein S. In the degradation of FVa by APC, the protein S/Gas6 chimera was only slightly less efficient than wild‐type protein S. In contrast, the protein S/Gas6 chimera expressed no FV‐dependent APC‐cofactor activity in a FVIIIa‐degradation system. This demonstrates the SHBG‐like region to be important for expression of APC‐cofactor activity of protein S and suggests that the SHBG‐like region of protein S interacts with FV during the APC‐mediated inactivation of FVIIIa.

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