Human CD46, or membrane cofactor protein, is a regulator of complement activation and is used as a cellular receptor by measles virus. Using a series of 13 single point mutants, the region of short consensus repeat (SCR) 2 domain involved in the regulation of complement activation was mapped to residues E84, N94, Y98, E102, E103, I104 and E108. Molecular modelling localized all residues, with the exception of E84, close to each other on the external lateral face of the molecule, away from the residues important for the binding of measles virus, which are localized on the top of the molecule. The E84 residues is localized in the SCR1-2 hinge and the deleterious effect of its substitution by an alanine residue could affect the relative orientation and / or tilt of SCR1 on SCR2. Taken together, the results suggest that the measles virus binding and cofactor activity of CD46 map to distinct areas on the SCR2 module.