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 for these two domains were derived based on the NMR structures of two CCP modules of factor H. Both CD46 modules are about 35 A long, and form a five-stranded antiparallel beta-barrel structure. Monte Carlo simulations, sampling the backbone torsion angles of the linker peptide and selecting possible orientations on the basis of minimal solvent-exposed hydrophobic area, were used to predict the orientation of CCP-I relative to CCP-II. We tested this procedure successfully for factor H. For CD46, three clusters of structures differing in the tilt angle of the two domains were obtained. To test these models, we mutagenized the CCP modules. Four proteins, two without an oligosaccharide chain and two with mutated short amino acid segments, reached the cell surface efficiently. Only the protein without the CCP-I oligosaccharide chain maintained binding to the viral attachment protein hemagglutinin. These results are consistent with one of our models and suggest that the viral hemagglutinin does not bind at the membrane-distal tip of CD46, but near the concave CCP-II interface region.
Mumenthaler
C
C
Institut für Molekularbiologie und Biophysik, ETH-Hönggerberg, Zürich, Switzerland.
Schneider
U
U
Buchholz
C J
CJ
Koller
D
D
Braun
W
W
Cattaneo
R
R
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D002459:Cell Fusion; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000378:metabolism*; D008459:Measles virus / Q000378:metabolism*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D009844:Oligosaccharides / Q000737:chemistry; D011485:Protein Binding; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D015703:Antigens, CD; D006389:Hemagglutinins, Viral; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D009844:Oligosaccharides; D011991:Receptors, Virus