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J Biol Chem, Vol. 274, Issue 21, 15144-15150, May 21, 1999

Interaction between Protein S and Complement C4b-binding Protein (C4BP)
AFFINITY STUDIES USING CHIMERAS CONTAINING C4BP -CHAIN SHORT CONSENSUS REPEATS

From the Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands and the Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands

Human C4b-binding protein (C4BP) is a regulator of the complement system and plays an important role in the regulation of the anticoagulant protein C pathway. C4BP can bind anticoagulant protein S, resulting in a decreased cofactor function of protein S for activated protein C. C4BP is a multimeric protein containing several identical -chains and a single -chain (C4BP), each chain being composed of short consensus repeats (SCRs). Previous studies have localized the protein S binding site to the NH₂-terminal SCR (SCR-1) of C4BP. To further localize the protein S binding site, we constructed chimeras containing C4BP SCR-1, SCR-2, SCR-3, SCR-1+2, SCR-1+3, and SCR-2+3 fused to tissue-type plasminogen activator. Binding assays of protein S with these chimeras indicated that SCR-2 contributes to the interaction of protein S with SCR-1, since the affinity of protein S for SCR-1+2 was up to 5-fold higher compared with SCR-1 and SCR-1+3. Using an assay that measures protein S cofactor activity, we showed that cofactor activity was decreased due to binding to constructs that contain SCR-1. SCR-1+2 inhibited more potently than SCR-1 and SCR-1+3. SCR-3 had no additional effect on SCR-1, and therefore the effect of SCR-2 was specific. In conclusion, -chain SCR-2 contributes to the interaction of C4BP with protein S.

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