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  • 标题:Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b
  • 本地全文:下载
  • 作者:Thomas H. Sharp ; Aimee L. Boyle ; Christoph A. Diebolder
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2019
  • 卷号:116
  • 期号:24
  • 页码:11900-11905
  • DOI:10.1073/pnas.1901841116
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要: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.
  • 关键词:complement ; IgM ; C1 ; cryoelectron tomography ; subtomogram averaging
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