title: The SHBG-like region of protein S is crucial for factor V-dependent APC-cofactor function.
abstract: Activated protein C (APC) regulates blood coagulation by degrading factor Va (FVa) and factor VIIIa (FVIIIa). Protein S is a cofactor to APC in the FVa degradation, whereas FVIIIa degradation is potentiated by the synergistic APC-cofactor activity of protein S and factor V (FV). To elucidate the importance of the sex-hormone-binding globulin (SHBG)-like region in protein S for expression of anticoagulant activity, a recombinant protein S/Gas6 chimera was constructed. It comprised the amino-terminal half of protein S and the SHBG-like region of Gas6, a structurally similar protein having no known anticoagulant properties. The protein S/Gas6 chimera expressed 40-50%, APC-cofactor activity in plasma as compared to wild-type protein S. In the degradation of FVa by APC, the protein S/Gas6 chimera was only slightly less efficient than wild-type protein S. In contrast, the protein S/Gas6 chimera expressed no FV-dependent APC-cofactor activity in a FVIIIa-degradation system. This demonstrates the SHBG-like region to be important for expression of APC-cofactor activity of protein S and suggests that the SHBG-like region of protein S interacts with FV during the APC-mediated inactivation of FVIIIa.
authors.affiliation: Department of Clinical Chemistry, Lund University, University Hospital, Malmö, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Nyberg
authors.forename: B
authors.initials: B
authors.lastname: Dahlbäck
authors.forename: P
authors.initials: P
authors.lastname: García de Frutos
mesh_terms: D005165:Factor V / Q000494:pharmacology*; D015944:Factor VIIIa / Q000378:metabolism; D015943:Factor Va / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D010314:Partial Thromboplastin Time; D011486:Protein C / Q000502:physiology*; D017293:Protein S / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D005165:Factor V; D015944:Factor VIIIa; D015943:Factor Va; D036341:Intercellular Signaling Peptides and Proteins; D011486:Protein C; D017293:Protein S; D011506:Proteins; D011993:Recombinant Fusion Proteins; D012738:Sex Hormone-Binding Globulin; D000099255:Growth Arrest-Specific Protein 6