Interaction between serum amyloid P component and C4b-binding protein associated with inhibition of factor I-mediated C4b degradation.
Serum amyloid P component (SAP) is a member of the pentraxin protein family. Although present in all types of amyloid deposits, it is also a normal constituent of blood and extravascular tissues. In blood, SAP forms a calcium-dependent, noncovalent complex with C4b-binding protein (C4BP). C4BP regulates the classical complement pathway as it binds C4b and functions as cofactor in its degradation by factor I. Although SAP and C4b bind to distinct sites on C4BP, it is not known whether the SAP-C4BP interaction affects the function of C4BP. We report that in a fluid phase system, SAP inhibited degradation of C4(H2O) (which is C4b-like) in a dose-dependent manner. Phosphorylethanolamine was found to alleviate the inhibitory effect of SAP on C4(H2O) degradation. Because this compound is known to inhibit the SAP-C4BP interaction, this indicated direct binding of SAP to C4BP to be required for inhibition of C4(H2O) degradation. Even though C4BP, C4(H2O), and SAP form a multimolecular complex in fluid phase, SAP was found to inhibit binding of C4BP to immobilized C4(H2O). The inhibitory effect was calcium dependent and alleviated by phosphorylethanolamine. Heparin, which is known to inhibit the interaction between SAP and C4BP, was also found to counteract the inhibitory effect of SAP on C4BP binding to C4(H2O). However, the effect of heparin was biphasic because high concentrations of heparin directly inhibited binding of C4(H2O) to C4BP. The inhibition of C4BP function by SAP suggests that SAP may be involved in regulation of the classical complement pathway C3 convertase.
García de Frutos
P
P
Department of Clinical Chemistry, University of Lund, Malmö General Hospital, Sweden.
Dahlbäck
B
B
D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D015935:Complement C4b / Q000378:metabolism*; D017244:Complement Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003169:Complement Inactivator Proteins; D004983:Ethanolamines / Q000494:pharmacology; D006023:Glycoproteins; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D011485:Protein Binding; D000683:Serum Amyloid P-Component / Q000378:metabolism* / Q000494:pharmacology
D002352:Carrier Proteins; D003169:Complement Inactivator Proteins; D004983:Ethanolamines; D006023:Glycoproteins; D000683:Serum Amyloid P-Component; C005448:phosphorylethanolamine; D015935:Complement C4b; D006493:Heparin; D017244:Complement Factor I; D002118:Calcium