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Evidence for distinct complement regulatory and measles virus binding sites on CD46 SCR2
D Christiansen1, G Deléage, D Gerlier
1Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Lyon RTH Laennec, Lyon, France.
European Journal of Immunology
|November 28, 2000
Summary
Human CD46 (membrane cofactor protein) regulates complement activation and binds measles virus. Studies show distinct regions on the SCR2 domain are responsible for these separate functions, mapping cofactor activity to one area and viral binding to another.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- Human CD46, also known as membrane cofactor protein, is a key regulator of complement activation.
- CD46 also serves as the cellular receptor for the measles virus, mediating viral entry.
Purpose of the Study:
- To identify the specific regions within the short consensus repeat (SCR) 2 domain of CD46 responsible for complement regulation.
- To determine if these regions overlap with the binding site for the measles virus.
Main Methods:
- Generated 13 single point mutants of the CD46 SCR2 domain.
- Utilized molecular modeling to localize mutated residues.
- Assessed the impact of mutations on complement regulatory function and viral binding.
Main Results:
- Mapped complement regulatory activity to residues E84, N94, Y98, E102, E103, I104, and E108 within the SCR2 domain.
- Molecular modeling revealed these residues, except E84, cluster on the lateral face of CD46, distinct from the measles virus binding site.
- Residue E84, located in the SCR1-2 hinge, influences the orientation of SCR1 on SCR2.
Conclusions:
- CD46's cofactor activity and measles virus binding function are mediated by distinct topographical areas on the SCR2 module.
- The findings provide a structural basis for understanding CD46's dual roles in innate immunity and viral pathogenesis.
