Crystal structure of two CD46 domains reveals an extended measles virus-binding surface.
Measles virus is a paramyxovirus which, like other members of the family such as respiratory syncytial virus, is a major cause of morbidity and mortality worldwide. The cell surface receptor for measles virus in humans is CD46, a complement cofactor. We report here the crystal structure at 3.1 A resolution of the measles virus-binding fragment of CD46. The structure reveals the architecture and spatial arrangement of two glycosylated short consensus repeats with a pronounced interdomain bend and some flexibility at the domain interface. Amino acids involved in measles virus binding define a large, glycan-free surface that extends from the top of the first to the bottom of the second repeat. The extended virus-binding surface of CD46 differs strikingly from those reported for the human virus receptor proteins CD4 and intercellular cell adhesion molecule-1 (ICAM-1), suggesting that the CD46 structure utilizes a novel mode of virus recognition. A highly hydrophobic and protruding loop at the base of the first repeat bears a critical virus-binding residue, thereby defining an important recognition epitope. Molecules that mimic the conformation of this loop potentially could be effective anti-viral agents by preventing binding of measles virus to CD46.
Casasnovas
J M
JM
Department of Biosciences at NOVUM, Karolinska Institute, 14157 Huddinge, Sweden.
Larvie
M
M
Stehle
T
T
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry; D016384:Consensus Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D006031:Glycosylation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry; D008459:Measles virus / Q000378:metabolism*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011991:Receptors, Virus / Q000737:chemistry* / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid
D015703:Antigens, CD; D015704:CD4 Antigens; C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011991:Receptors, Virus; D018799:Intercellular Adhesion Molecule-1