UC San Diego

The M protein is the major surface-associated virulence factor of Group A Streptococcus (GAS). M protein is predicted to be a parallel α-helical coiled coil, as identified by a heptad repeat pattern with small, hydrophobic residues at the first and fourth positions. To date, over 200 M variants have been identified, however a common trend among M proteins is that they contain regions characterized as non-ideal coiled coils, with both destabilizing residues in the putative dimer interface and skips and insertions in the heptad pattern. Crystallographic studies on M1 revealed two distinct registers at the fibrinogen (Fg) binding sites: a Fg non-binding register 1 and a Fg-binding register 2. These conformations are related by a rotation of one helical face, resulting in the exposure of adjacent faces of the coiled coil. It was previously found that mutations stabilizing register 1 understandably reduced interaction with Fg. However, we now report that mutations stabilizing register 2 also reduce Fg binding. These results suggest that dynamic motion in M1 is required for association with Fg, in a “lure-and-catch” model. This requirement for binding offers a novel explanation for the presence of non-ideal coiled coil structure in M1, a feature that is evolutionarily conserved among M proteins in general.

The M1 protein contains three fibrinogen binding sites, one in the A region and two in the B repeats. Both binding sites in the B repeats are essential to establish a supramolecular complex capable of activating neutrophils. However the function of the binding site in the A region is still unknown. In addition to contributing to immune activation, the M1-fibrinogen interaction contributes to immune evasion. Surface recruitment of fibrinogen has been shown to protect against complement deposition and subsequent phagocytosis. We investigated the role of each fibrinogen binding site in conferring protection from phagocytosis.