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Volume 272, Number 23, Issue of June 6, 1997 pp. 14658-14665
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

A Region of Vitamin K-dependent Protein S That Binds to C4b Binding Protein (C4BP) Identified Using Bacteriophage Peptide Display Libraries

(Received for publication, September 23, 1996, and in revised form, March 24, 1997)

Sara Linse , Ylva Härdig ^¶ , David A. Schultz and Björn Dahlbäck ^¶

From the  Department of Physical Chemistry 2, Lund University, S-221 00 Lund, Sweden, the ^¶ Department of Clinical Chemistry, Lund University, University Hospital Malmö, S-205 02 Malmö, Sweden, and the  Biology Department, University of California at San Diego, La Jolla, California 92093-0649

Vitamin K-dependent protein S, a blood coagulation inhibitor, interacts with the C4b-binding protein (C4BP) in human plasma with high affinity (K_D = 0.1 nM). Identification of a portion of protein S that binds to C4BP has been approached using random libraries of 6- and 15-mer peptides displayed on bacteriophage surfaces. Bacteriophage binding to the -chain of C4BP were selected in several rounds of affinity purification with intervening amplification in E. coli. Homology searches of the affinity purified peptide sequences against protein S led to the identification of four regions in protein S that were similar to several of the selected peptides. These regions were synthesized as linear peptides and tested in inhibition experiments. Only one distinct peak (around position 450) was observed when the homology scores versus human protein S sequence were averaged over all affinity purified peptides. A synthetic peptide comprising residues 439-460 in human protein S was found to inhibit protein S binding to C4BP. The same result was found with two overlapping peptides (residues 447-468 and 435-468, respectively) in a second set of synthetic peptides. Direct binding of the peptides to C4BP was inferred from titrations monitored by recording the near UV circular dichroism spectra or the polarization of tryptophan fluorescence. The results suggest that residues 447-460 constitute a portion of protein S that is important for the interaction with C4BP. These findings may have implications for patients suffering from thrombosis, due to the lack of free protein S, by directing the design of drugs that disrupt protein S binding to C4BP.

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