HIGHLY VARIABLE REGION IN MEMBERS OF THE STREPTOCOCCAL M-PROTEIN FAMILY BINDS THE HUMAN-COMPLEMENT REGULATOR C4BP

Strains of Streptococcus pyogenes express one or more molecules that a re members of the M protein family, a group of surface proteins implic ated in virulence. A characteristic property of the molecules in this family is the presence of a highly variable N-terminal region, whose f unction is unknown. Here we show that human C4b-binding protein (C4BP) , a regulatory component of the complement system, binds to the highly variable region of many members of the M protein family. Chimeric mol ecules, in which the N-terminal regions of four different C4BP-binding proteins were combined with the C-terminal part of the nonbinding M5 protein, had intact C4BP-binding ability, as judged by binding assays and Scatchard analysis with highly purified molecules, Moreover, work with the C4BP-binding Arp4 protein showed that an N-terminal 52-residu e fragment retained binding ability, and that a 21-residue synthetic p eptide derived from the variable region completely inhibited the bindi ng of C4BP, Computer-assisted analysis of the four C4BP-binding region s studied here (45-66 amino acid residues) indicated that they lack re sidue identities that could explain their ability to bind the same lig and, but differ from the nonbinding M5 protein in their lower propensi ty to form a coiled-coil. Thus, the variable C4BP-binding regions have an extraordinary capacity for sequence variation, while retaining the ability to bind C4BP. These data indicate that an important function of the variable region in members of the M protein family is to bind a host protein that down-regulates the complement system.