Vitamin K-dependent protein S localizing complement regulator C4b-binding protein to the surface of apoptotic cells.
Apoptosis is characterized by a lack of inflammatory reaction in surrounding tissues, suggesting local control of complement activation. During the initial stage of apoptosis, cells expose negatively charged phospholipid phosphatidylserine on their surfaces. The vitamin K-dependent protein S has a high affinity for this type of phospholipid. In human plasma, 60-70% of protein S circulates in complex with C4b-binding protein (C4BP). The reason why protein S and C4BP form a high-affinity complex in plasma is not known. However, C4BP is an important regulator of the classical pathway of the complement system where it acts as a cofactor in degradation of complement protein C4b. Using Jurkat cells as a model system for apoptosis, we now show protein S to bind to apoptotic cells. We further demonstrate protein S-mediated binding of C4BP to apoptotic cells. Binding of the C4BP-protein S complex to apoptotic cells was calcium-dependent and could be blocked with Abs directed against the phospholipid-binding domain in protein S. Annexin V, which binds to exposed phosphatidylserine on the apoptotic cell surface, could inhibit the binding of protein S. The C4BP that was bound via protein S to the apoptotic cells was able to interact with the complement protein C4b, supporting a physiological role of the C4BP/protein S complex in regulation of complement on the surface of apoptotic cells.
Webb
Joanna H
JH
Division of Clinical Chemistry, Department of Laboratory Medicine, University Hospital Malmö, Lund University, Sweden.
Blom
Anna M
AM
Dahlbäck
Björn
B
D015055:1-Carboxyglutamic Acid / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism*; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D046911:Macromolecular Substances; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017293:Protein S / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011951:Receptors, Complement / Q000378:metabolism*; D014812:Vitamin K / Q000502:physiology
D017304:Annexin A5; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D046911:Macromolecular Substances; D010743:Phospholipids; D017293:Protein S; D011951:Receptors, Complement; D014812:Vitamin K; D015055:1-Carboxyglutamic Acid; D015935:Complement C4b