Molecular Basis for the Interaction of Low Density Lipoprotein Receptor-related Protein 1 (LRP1) with Integrin αMβ2 IDENTIFICATION OF BINDING SITES WITHIN αMβ2 FOR LRP1

The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that controls macrophage migration in part by interacting with beta(2) integrin receptors. However, the molecular mechanism underlying LRP1 integrin recognition is poorly understood. Here, we report that LRP1 specifically recognizes alpha(M)beta(2) but not its homologous receptor alpha(L)beta(2). The interaction between these two cellular receptors in macrophages is significantly enhanced upon alpha(M)beta(2) activation by LPS and is mediated by multiple regions in both LRP1 and alpha(M)beta(2). Specifically, we find that both the heavy and light chains of LRP1 are involved in alpha(M)beta(2) binding. Within the heavy chain, the binding is mediated primarily via the second and fourth ligand binding repeats. For alpha(M)beta(2), we find that the alpha(M)-I domain represents a major LRP1 recognition site. Indeed, substitution of the I domain of the alpha(L)beta(2) receptor with that of alpha(M) confers the alpha(L)beta(2) receptor with the ability to interact with LRP1. Furthermore, we show that residues (160)EQLKKSKTL(170) within the alpha(M)-I domain represent a major LRP1 recognition site. Given that perturbation of this specific sequence leads to altered adhesive activity of alpha(M)beta(2), our finding suggests that binding of LRP1 to alpha(M)beta(2) could alter integrin function. Indeed, we further demonstrate that the soluble form of LRP1 (sLRP1) inhibits alpha(M)beta(2)-mediated adhesion of cells to fibrinogen. These studies suggest that sLRP1 may attenuate inflammation by modulating integrin function.