Article: article from journal or magazin.
Molecular analysis of the interaction of LCMV with its cellular receptor [alpha]-dystroglycan.
Journal of Cell Biology
alpha-Dystroglycan (DG) has been identified as the cellular receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus (LFV). This subunit of DG is a highly versatile cell surface molecule that provides a molecular link between the extracellular matrix (ECM) and a beta-DG transmembrane component, which interacts with the actin-based cytoskeleton. In addition, DG exhibits a complex pattern of interaction with a wide variety of ECM and cellular proteins. In the present study, we characterized the binding of LCMV to alpha-DG and addressed the role of alpha-DG-associated host-derived proteins in virus infection. We found that the COOH-terminal region of alpha-DG's first globular domain and the NH2-terminal region of the mucin-related structures of alpha-DG together form the binding site for LCMV. The virus-alpha-DG binding unlike ECM alpha-DG interactions was not dependent on divalent cations. Despite such differences in binding, LCMV and laminin-1 use, in part, an overlapping binding site on alpha-DG, and the ability of an LCMV isolate to compete with laminin-1 for receptor binding is determined by its binding affinity to alpha-DG. This competition of the virus with ECM molecules for receptor binding likely explains the recently found correlation between the affinity of LCMV binding to alpha-DG, tissue tropism, and pathological potential. LCMV strains and variants with high binding affinity to alpha-DG but not low affinity binders are able to infect CD11c+ dendritic cells, which express alpha-DG at their surface. Infection followed by dysfunction of these antigen-presenting cells contributes to immunosuppression and persistent viral infection in vivo.
Animals, Arenaviridae Infections/metabolism, Arenaviridae Infections/virology, Binding Sites, Binding, Competitive, Cells, Cultured, Cytoskeletal Proteins/chemistry, Cytoskeletal Proteins/metabolism, Dystroglycans, Extracellular Matrix Proteins/chemistry, Extracellular Matrix Proteins/metabolism, Female, Laminin/metabolism, Lymphocytic choriomeningitis virus/isolation & purification, Lymphocytic choriomeningitis virus/metabolism, Membrane Glycoproteins/chemistry, Membrane Glycoproteins/metabolism, Mice, Mice, Inbred C57BL, Protein Structure, Tertiary, Spleen/metabolism, Spleen/virology
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