The C4b-binding protein-protein S interaction is hydrophobic in nature.

C4b-binding protein (C4BP) is a major regulatory molecule of the complement system. By forming a non covalent complex with the anticoagulant cofactor protein S (PS), it also plays an important role in blood coagulation. C4BP is composed of one beta-chain and seven alpha-chains that are essentially built from complement control protein (CCP)-modules. Our group has previously reported that the first (N-terminal) CCP module of the beta-chain (betaCCP1) contains the entire binding site for protein S. We now investigate further the binding of protein S to C4BP and show that the complex formation is essentially dependent on hydrophobic forces with minor contribution from electrostatic interactions. This result is in agreement with homology modeling experiments carried out in conjunction with inter-species sequence comparison and theoretical enumeration of potential binding sites. These methods pinpoint a solvent exposed hydrophobic cluster at the surface of the betaCCP1 module that is of crucial importance for the binding process.