title: Distinct kinetics for binding of the CD46 and SLAM receptors to overlapping sites in the measles virus hemagglutinin protein.
abstract: Measles virus (MV) is a human pathogen using two distinct cell surface receptors for entry into host cells. We present here a comparative analysis for binding of the MV receptors CD46 and SLAM to the measles virus hemagglutinin protein (MVH, Edmonston strain). Soluble monomeric and dimeric MVH variants were prepared in mammalian cells and their conformation assessed using a panel of monoclonal antibodies. The two receptor molecules specifically bound to the MVH protein with distinct binding modes. The association rate (k(a)) for SLAM binding to MVH was very low ( approximately 3000 m(-1)s(-1)), about 20 times lower that the k(a) determined for CD46 binding. However, SLAM bound tighter to the virus protein than CD46, as revealed by a 5-fold lower dissociation rate (k(d), approximately 1.5 x 10(-3) s(-1)). These data suggest that the SLAM receptor binds to a less accessible and more hydrophobic surface on MVH than the CD46 receptor, as illustrated in a binding model. Despite the differences in kinetics, receptor competition binding experiments revealed that they recognize overlapping sites in MVH. Indeed, a panel of anti-MVH monoclonal antibodies equally inhibited binding of both receptor molecules. The similar immune reactivity of the two receptor binding sites suggests that the shift in receptor usage by MV may not be driven by immune responses.
authors.affiliation: Department of Biosciences at NOVUM, Karolinska Institutet, Center for Biotechnology, S141 57 Huddinge, Sweden.
authors.forename: Cesar
authors.initials: C
authors.lastname: Santiago
authors.forename: Ewa
authors.initials: E
authors.lastname: Björling
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
authors.forename: José M
authors.initials: JM
authors.lastname: Casasnovas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D019281:Dimerization; D014644:Genetic Variation; D006023:Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007145:Immunoglobulin kappa-Chains; D007136:Immunoglobulins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D007700:Kinetics; D008459:Measles virus / Q000502:physiology*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface; D011991:Receptors, Virus / Q000276:immunology / Q000502:physiology; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497857:CD46 protein, human; D006023:Glycoproteins; D006389:Hemagglutinins, Viral; D007145:Immunoglobulin kappa-Chains; D007136:Immunoglobulins; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1