Summary
The protein C anticoagulant system provides important control of the blood coagulation
cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated
to a serine protease by the thrombin-thrombomodulin complex on endothelial cells.
Activated protein C functions by degrading the phospholipid-bound coagulation factors
Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent
protein with multiple domains. From the N-terminal it contains a vitamin K-dependent
domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains
and a C-terminal region homologous to the androgen binding proteins. Three different
types of post-translationally modified amino acid residues are found in protein S,
11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated
aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each
of the other three EGF-like domains. The EGF-like domains contain very high affinity
calcium binding sites, and calcium plays a structural and stabilising role. The importance
of the anticoagulant properties of protein S is illustrated by the high incidence
of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation
may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins
in the complement system, the C4b-binding protein (C4BP). The complexed form of protein
S has no APC cofactor function. C4BP is a high molecular weight multimeric protein
with a unique octopus-like structure. It is composed of seven identical α-chains and
one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning
of the β-chain showed the α- and β-chains to be homologous and of common evolutionary
origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement
or consensus repeats, SCR) and their genes are located in close proximity on chromosome
1, band 1q32. Available experimental data suggest the β-chain to contain the single
protein S binding site on C4BP, whereas each of the α-chains contains a binding site
for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein
S, the β-chain is required for protein S binding, but not for the assembly of the
α-chains during biosynthesis. Protein S has a high affinity for negatively charged
phospholipid membranes, and is instrumental in binding C4BP to negatively charged
phospholipid. This constitutes a novel mechanism for control of the complement system
on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved
in yet another calcium-dependent protein-protein interaction with a protein known
as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and
SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is
a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It
is homologous to C reactive protein (CRP) but its function is not yet known. The specific
high affinity interactions between protein S, C4BP and SAP suggest the regulation
of blood coagulation and that of the complement system to be closely linked.
