A 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 are members of the M protein family, a group of surface proteins implicated in virulence. A characteristic property of the molecules in this family is the presence of a highly variable N-terminal region, whose function 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 molecules, in which the N-terminal regions of four different C4BP-binding proteins were combined with the C-terminal part of the non-binding 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-residue fragment retained binding ability, and that a 21-residue synthetic peptide derived from the variable region completely inhibited the binding of C4BP. Computer-assisted analysis of the four C4BP-binding regions studied here (45-66 amino acid residues) indicated that they lack residue identities that could explain their ability to bind the same ligand, but differ from the nonbinding M5 protein in their lower propensity 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.
Johnsson
E
E
Department of Medical Microbiology, Lund University, Sweden.
Thern
A
A
Dahlbäck
B
B
Hedén
L O
LO
Wikström
M
M
Lindahl
G
G
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D016167:Integrin alphaXbeta2; D008969:Molecular Sequence Data; D011485:Protein Binding; D013297:Streptococcus pyogenes / Q000737:chemistry
D000942:Antigens, Bacterial; C062462:Arp4 protein, Streptococcus pyogenes; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002352:Carrier Proteins; D016167:Integrin alphaXbeta2; C014689:streptococcal M protein