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J. Biol. Chem., Vol. 265, Issue 14, 8127-8135, May, 1990
B Dahlback, B Hildebrand and J Malm
Vitamin K-dependent protein S is an anticoagulant plasma protein
functioning as a cofactor to activated protein C in the degradation of
coagulation factors Va and VIIIa. To determine which regions in protein S
are important for its cofactor activity, we have raised and characterized a
large panel of monoclonal antibodies against human protein S. Several of
the antibodies were directed against Ca2(+)- dependent epitopes, and they
were found to be located either in the domain containing
gamma-carboxyglutamic acid (Gla), the thrombin- sensitive region, or in the
first epidermal growth factor (EGF)-like domain. The first two types of
epitopes were exposed at approximately 1 mM Ca2+, whereas the epitope(s) in
the EGF-like domains required less than 1 microM Ca2+, suggesting the
presence of one or more high affinity Ca2(+)-binding site(s). The
antibodies, as well as their Fab' fragments, against all three types of
Ca2(+)-dependent epitopes efficiently inhibited the activated protein C
cofactor function of protein S, but through different mechanisms. The
antibodies against the Gla domain exerted their effects through inhibition
of protein S binding to negatively charged phospholipid. Fab'-fragments of
antibodies against the thrombin-sensitive region and the first EGF-like
domain were the most potent inhibitors of the activated protein C cofactor
function but did not inhibit phospholipid binding of protein S. In
conclusion, we have identified the domains in protein S that are important
for the activated protein C cofactor activity. The Gla domain is
instrumental in the binding of protein S to phospholipid, whereas the
thrombin-sensitive region and the first EGF-like domain may be directly
involved in protein-protein interactions on the phospholipid surface.
Characterization of functionally important domains in human vitamin K- dependent protein S using monoclonal antibodies
Department of Clinical Chemistry, University of Lund, Malmo General Hospital, Sweden.
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