Molecular Basis for the Interaction of Low Density Lipoprotein Receptor-related Protein 1 (LRP1) with Integrin αMβ2

Abstract

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