Two clusters of acidic amino acids at the NH¦2-terminus of complement component C4 Ã'-chain are important for C2 binding

grantor: University of TorontoCleavage of complement component C3 into C3a and C3b is a critical step in the activation of the complement system and consequently the role of this system in host defense. The reaction is catalyzed by two homologous enzymes, the classical and alternative pathway C3 convertases, which have the compositions C4b2a and C3bBb, respectively. The goal of this thesis was to identify sequences in human complement component C4 that contribute to the binding of C2. Previous mapping studies using monoclonal antibodies have suggested that the 738-826 segment at the NH2-terminus of C4 Ã'-chain is involved in the interaction with C4BP, a ligand of C4b which is antagonistic to the binding of C2. Mapping studies on C3, particularly using the site-directed mutagenesis approach, have also identified an acidic amino acid segment at the NH2-terminus of C3 Ã'-chain as being essential for the interaction with factor B, the alternative pathway C2 analogue. Due to the functional similarity between C4 and C3 and the significant sequence similarity at the NH2-termini of their respective à '-chains, this segment of C4 was therefore hypothesized to contribute to the binding of C2. (Abstract shortened by UMI.)M.Sc