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 β2 integrin receptors. However, the molecular mechanism underlying LRP1 integrin recognition is poorly understood. Here, we report that LRP1 specifically recognizes αMβ2 but not its homologous receptor αLβ2. The interaction between these two cellular receptors in macrophages is significantly enhanced upon αMβ2 activation by LPS and is mediated by multiple regions in both LRP1 and αMβ2. Specifically, we find that both the heavy and light chains of LRP1 are involved in αMβ2 binding. Within the heavy chain, the binding is mediated primarily via the second and fourth ligand binding repeats. For αMβ2, we find that the αM-I domain represents a major LRP1 recognition site. Indeed, substitution of the I domain of the αLβ2 receptor with that of αM confers the αLβ2 receptor with the ability to interact with LRP1. Furthermore, we show that residues 160EQLKKSKTL170 within the αM-I domain represent a major LRP1 recognition site. Given that perturbation of this specific sequence leads to altered adhesive activity of αMβ2, our finding suggests that binding of LRP1 to αMβ2 could alter integrin function. Indeed, we further demonstrate that the soluble form of LRP1 (sLRP1) inhibits αMβ2-mediated adhesion of cells to fibrinogen. These studies suggest that sLRP1 may attenuate inflammation by modulating integrin function.