Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement

Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibo...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2018-02, Vol.359 (6377), p.794-797
Main Authors: Ugurlar, Deniz, Howes, Stuart C, de Kreuk, Bart-Jan, Koning, Roman I, de Jong, Rob N, Beurskens, Frank J, Schuurman, Janine, Koster, Abraham J, Sharp, Thomas H, Parren, Paul W H I, Gros, Piet
Format: Article
Language:English
Subjects:
Alarmins - chemistry
Alarmins - ultrastructure
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - ultrastructure
Avidity
Binding Sites
Complement
Complement Activation
Complement C1 - chemistry
Complement C1 - ultrastructure
Complement component C1
Complement component C1q
Cryoelectron Microscopy
Damage
Electron microscopy
Hazards
Hexamers
Humans
Immune clearance
Immune response
Immune system
Immunoglobulin G
Immunoglobulin G - chemistry
Immunoglobulin G - genetics
Immunoglobulin G - ultrastructure
Immunoglobulins
Initiation complex
Innate immunity
Microscopy
Monoclonal antibodies
Mutagenesis
Pattern recognition
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Summary:Danger patterns on microbes or damaged host cells bind and activate C1, inducing innate immune responses and clearance through the complement cascade. How these patterns trigger complement initiation remains elusive. Here, we present cryo-electron microscopy analyses of C1 bound to monoclonal antibodies in which we observed heterogeneous structures of single and clustered C1-immunoglobulin G1 (IgG1) hexamer complexes. Distinct C1q binding sites are observed on the two Fc-CH2 domains of each IgG molecule. These are consistent with known interactions and also reveal additional interactions, which are supported by functional IgG1-mutant analysis. Upon antibody binding, the C1q arms condense, inducing rearrangements of the C1r s proteases and tilting C1q's cone-shaped stalk. The data suggest that C1r may activate C1s within single, strained C1 complexes or between neighboring C1 complexes on surfaces.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aao4988