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Decay accelerating activity of complement receptor type 1 (CD35). Two active sites are required for dissociating C5
M Krych-Goldberg1, R E Hauhart, V B Subramanian
1Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
The Journal of Biological Chemistry
|October 26, 1999
Summary
This study identified key sites on CR1 (complement receptor 1) that control complement convertase activity. Site 1 is crucial for C3 convertase dissociation, while both Site 1 and Site 2 are needed for efficient C5 convertase regulation.
Area of Science:
- Immunology
- Complement System Biology
Background:
- The complement system is a crucial part of innate immunity.
- Complement receptor 1 (CR1) plays a regulatory role in complement activation.
- Understanding CR1's function in C3 and C5 convertase regulation is vital.
Purpose of the Study:
- To pinpoint the specific regions within CR1 responsible for dissociating C3 and C5 convertases.
- To characterize the distinct roles of different CR1 domains in complement regulation.
Main Methods:
- Generation of truncated CR1 derivatives containing complement control protein repeats (CCPs).
- Assays to measure decay accelerating activity on C3 and C5 convertases.
- Homologous substitution mutagenesis to identify critical residues.
Main Results:
- Site 1 (CCPs 1-3) effectively accelerates the decay of C3 convertases.
- Site 2 exhibits lower C3 convertase decay activity compared to Site 1.
- Efficient C5 convertase decay requires both Site 1 and Site 2, with Site 1 being primary.
- Mutagenesis identified key residues in Site 1 for dissociation activity.
Conclusions:
- CR1's Site 1 is the primary mediator of C5 convertase decay acceleration.
- Site 2 plays an auxiliary role in C5 convertase regulation, potentially via C3b binding.
- Engineered CR1 variants show enhanced C3 convertase decay accelerating activity.
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