A 3D MODEL FOR THE MEASLES-VIRUS RECEPTOR CD46 BASED ON HOMOLOGY MODELING, MONTE-CARLO SIMULATIONS, AND HEMAGGLUTININ BINDING-STUDIES

The two terminal complement control protein (CCP) modules of the CD46 glycoprotein mediate measles virus binding. Three-dimensional models f or these two domains were derived based on the NMR structures of two C CP modules of factor H. Both CD46 CCP modules are about 35 Angstrom lo ng, and form a five-stranded antiparallel P-barrel structure. Monte Ca rlo simulations, sampling the backbone torsion angles of the linker pe ptide and selecting possible orientations on the basis of minimal solv ent-exposed hydrophobic area, were used to predict the orientation of CCP-I relative to CCP-II. We tested this procedure successfully for fa ctor H. For CD46, three clusters of structures differing in the tilt a ngle of the two domains were obtained. To test these models, we mutage nized the CCP modules. Four proteins, two without an oligosaccharide c hain and two with mutated short amino acid segments, reached the cell surface efficiently. Only the protein without the CCP-I oligosaccharid e chain maintained binding to the viral attachment protein hemagglutin in. These results are consistent with one of our models and suggest th at the viral hemagglutinin does not bind at the membrane-distal tip of CD46, but near the concave CCP-I-II interface region.