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J Biol Chem, Vol. 274, Issue 27, 19237-19245, July 2, 1999

A Cluster of Positively Charged Amino Acids in the C4BP -Chain Is Crucial for C4b Binding and Factor I Cofactor Function

The Wallenberg Laboratory, Department of Clinical Chemistry, Lund University, University Hospital Malmö, S-205 02 Malmö, Sweden

C4b-binding protein (C4BP) is a regulator of the classical complement pathway, acting as a cofactor to factor I in the degradation of C4b. Computer modeling and structural analysis predicted a cluster of positively charged amino acids at the interface between complement control protein modules 1 and 2 of the C4BP -chain to be involved in C4b binding. Three C4BP mutants, R39Q, R64Q/R66Q, and R39Q/R64Q/R66Q, were expressed and assayed for their ability to bind C4b and to function as factor I cofactors. The apparent affinities of R39Q, R64Q/R66Q, and R39Q/R64Q/R66Q for immobilized C4b were 15-, 50-, and 140-fold lower, respectively, than that of recombinant wild type C4BP. The C4b binding site demonstrated herein was also found to be a specific heparin binding site. In C4b degradation, the mutants demonstrated decreased ability to serve as factor I cofactors. In particular, the R39Q/R64Q/R66Q mutant was inefficient as cofactor for cleavage of the Arg⁹³⁷-Thr⁹³⁸ peptide bond in C4b. In contrast, the factor I mediated cleavage of Arg¹³¹⁷-Asn¹³¹⁸ bond was less affected by the C4BP mutations. In conclusion, we identify a cluster of amino acids that is part of a C4b binding site involved in the regulation of the complement system.

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