Journal Article

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

Ugurlar, Deniz, Parren, Paul W. H. I., Sharp, Thomas H., Koning, Roman I., Howes, Stuart C., Beurskens, Frank J., Schuurman, Janine, de Kreuk, Bart-Jan, Koster, Abraham J., Gros, Piet, de Jong, Rob N.

2018

Overview

In the classical complement pathway, the C1 initiation complex binds to danger patterns on the surface of microbes or damaged host cells and triggers an immune response. Immunoglobulin G (IgG) antibodies form hexamers on cell surfaces that have high avidity for the C1 complex. Ugurlar et al. used cryo–electron microscopy to show how a hexamer of C1 complexes interacts with the IgG hexamer. Structure-guided mutagenesis revealed how C1 is activated to trigger an immune response. Science , this issue p. 794 Cryo–electron microscopy structures suggest mechanisms for how danger patterns on cell membranes trigger an immune response. 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 2 s 2 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.

• Publisher: The American Association for the Advancement of Science
• Subject: 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