Distinct recognition of complement iC3b by integrins αXβ2 and αMβ2

Recognition by the leukocyte integrins alpha(X)beta(2) and alpha(M)beta(2) of complement iC3b-opsonized targets is essential for effector functions including phagocytosis. The integrin-binding sites on iC3b remain incompletely characterized. Here, we describe negative-stain electron microscopy and biochemical studies of alpha(X)beta(2) and alpha(M)beta(2) in complex with iC3b. Despite high homology, the two integrins bind iC3b at multiple distinct sites. alpha(X)beta(2) uses the aX aI domain to bind iC3b on its C3cmoiety at one of two sites: a major site at the interface between macroglobulin (MG) 3 and MG4 domains, and a less frequently used site near the C345C domain. In contrast, alpha(X)beta(2) uses its aI domain to bind iC3b at the thioester domain and simultaneously interacts through a region near the alpha(M) beta-propeller and beta(2) aI domain with a region of the C3c moiety near the C345C domain. Remarkably, there is no overlap between the primary binding site of alpha(X)beta(2) and the binding site of alpha(X)beta(2) on iC3b. Distinctive binding sites on iC3b by integrins alpha(X)beta(2) and alpha(M)beta(2) may be biologically beneficial for leukocytes to more efficiently capture opsonized pathogens and to avoid subversion by pathogen factors.