Dr. Oldstone and his colleagues have recently identified the putative receptor for measles virus (MV), the membrane cofactor protein CD46, a member of the regulators of complement activation family. MV is permissive for human and simian but not hamster or murine cells. However, CHO or murine MC57 and 3T3 cells barely permissive to MV become permissive and produce progeny virus when stably expressing any of the four CD46 isoforms. This occurs with Edmonston strain MV as well as field isolates. The CD46 molecule is composed of four short consensus repeats (SCR) of 60 amino acids each, an enriched serine, threonine and proline region and a transmembrane tail at the carboxy terminus. Only antibodies against SCR-1 and SCR-2 were effective at blocking MV binding and infectivity. In addition, mutants of CD46 mapped MV binding to the first and second but not the third and fourth SCR domain. the proposed research is to molecularly dissect CD46-MV interactions and study the biology and consequences of that interaction. First, mutant CD46 constructs will be generated, relevant peptides from CD46 and MV H protein will be synthesized and MV H protein will be solubilized to map out the specific sequences on CD46 SCR-1 and SCR-2 domains that serve as the MV receptor and on MV H protein that bind to CD46. Second these data will be used to develop molecules that compete with MV binding. SCR-1 domain of CD46 is not required for CD46 interaction with the complement system. Since SCR-1 has no known housekeeping role in cells, it may be possible to block viral attachment while maintaining functional integrity of the CD46 molecule.
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