IDENTIFICATION OF A DOMAIN IN HUMAN FACTOR-H AND FACTOR H-LIKE PROTEIN-1 REQUIRED FOR THE INTERACTION WITH STREPTOCOCCAL M-PROTEINS

The plasma protein factor H (FH) inhibits the alternative pathway of c omplement activation, Previous work has shown that FH binds to group A streptococci and that the interaction does not interfere with the com plement-inhibitory capacity of FH. In this work, we report a molecular analysis of this interaction, In absorption experiments with human pl asma, M protein-expressing group A streptococci bound both FH and FH-l ike protein-1 (FRL-1), an active 42-kDa splice product of the FH-gene transcript comprising the first 7 of its 20 short consensus repeat (SC R) domains, rFHL-1 also bound to M protein-expressing streptococci, bu t rFH fragments containing SCR 1-5 or SCR 1-6 did not, rFHL-1 bound to purified M5 protein with an affinity that was higher than the value c alculated for the interaction between FH and M5 protein, The binding o f radiolabeled rFHL-1 to immobilized M5 was blocked completely by unla beled rFHL-1, but was inhibited only partially by SCR 1-6, emphasizing the importance of SCR 7 for the interaction, In experiments with the FH-related proteins FHR-3 and FHR-4, only the former bound to M protei n-expressing streptococci, again pointing to an involvement of SCR 7, since FHR-3, but not FHR-4, contains a domain that is similar to SCR 7 , Finally, the interaction between rFHL-1 and purified M5 protein was inhibited by heparin, which binds FH via SCR 7, Together, these data i ndicate that the interaction between streptococcal M proteins and FH o r FHL-1 requires SCR 7.