T. Sharp, A. Boyle, C. Diebolder, A. Kros, A. Koster, P. Gros
Proceedings of the National Academy of Sciences, 2019
Significance IgM antibodies protect mammals against humoral microbial infection and mediate clearance of cellular debris. IgM activates the immune complement system only after binding to cell-surface antigens. Here we report the in situ 3D structures of surface-antigen–bound IgM antibodies in complex with both C1 and C4b complement components. The data indicate the structural arrangement of pentameric and hexameric IgM upon antigen binding, exposing the C1q-binding sites with both adopting hexagonal symmetry. The structures reveal the entire C1qr2s2 complex and elucidate several protein–protein interactions with C4b and IgM. Based on the structural data, we hypothesize a C1q-transmitted surface trigger that activates C1, leading to C4 cleavage and C4b deposition on membranes. Antigen binding by serum Ig-M (IgM) protects against microbial infections and helps to prevent autoimmunity, but causes life-threatening diseases when mistargeted. How antigen-bound IgM activates complement-immune responses remains unclear. We present cryoelectron tomography structures of IgM, C1, and C4b complexes formed on antigen-bearing lipid membranes by normal human serum at 4 °C. The IgM-C1-C4b complexes revealed C4b product release as the temperature-limiting step in complement activation. Both IgM hexamers and pentamers adopted hexagonal, dome-shaped structures with Fab pairs, dimerized by hinge domains, bound to surface antigens that support a platform of Fc regions. C1 binds IgM through widely spread C1q-collagen helices, with C1r proteases pointing outward and C1s bending downward and interacting with surface-attached C4b, which further interacts with the adjacent IgM-Fab2 and globular C1q-recognition unit. Based on these data, we present mechanistic models for antibody-mediated, C1q-transmitted activation of C1 and for C4b deposition, while further conformational rearrangements are required to form C3 convertases.
Cited by 32 publications.
Field of study: Medicine