title: Molecular basis for the interaction of low density lipoprotein receptor-related protein 1 (LRP1) with integrin alphaMbeta2: identification of binding sites within alphaMbeta2 for LRP1.
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.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201; Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Sripriya
authors.initials: S
authors.lastname: Ranganathan
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201; the Departments of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Cao
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Jason
authors.initials: J
authors.lastname: Catania
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Molly
authors.initials: M
authors.lastname: Migliorini
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201; the Departments of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: LiZhang@som.umaryland.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201; Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201; the Departments of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: dstrickland@som.umaryland.edu.
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D002460:Cell Line; D005340:Fibrinogen / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000737:chemistry*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012995:Solubility; D014162:Transfection
chemical_list: D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016177:Macrophage-1 Antigen; D005340:Fibrinogen