Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b

作者：T. Sharp, A. Boyle, C. Diebolder, A. Kros, A. Koster, P. Gros · 发表于：Proceedings of the National Academy of Sciences of the United States of America · 年份：2019 · DOI：10.1073/pnas.1901841116 · 被引用次数：160 · 研究领域：Chemistry、Medicine

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...