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TitleInsights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 116, Issue 24, Page 11900-11905, Year 2019
Publish dateJun 11, 2019
AuthorsThomas H Sharp / Aimee L Boyle / Christoph A Diebolder / Alexander Kros / Abraham J Koster / Piet Gros /
PubMed AbstractAntigen 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 ...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-Fab 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.
External linksProc Natl Acad Sci U S A / PubMed:31147461 / PubMed Central
MethodsEM (subtomogram averaging)
Resolution25.6 - 26.7 Å
Structure data

EMDB-4878:
In situ structure of a hexameric IgM complex bound to complement components C1 and two molecules of C4b
Method: EM (subtomogram averaging) / Resolution: 26.7 Å

EMDB-4943:
In situ structure of a pentameric IgM complex bound to complement components C1 and one molecule of C4b
Method: EM (subtomogram averaging) / Resolution: 25.6 Å

EMDB-4945:
In situ structure of a pentameric IgM complex bound to complement components C1 and two molecules of C4b
Method: EM (subtomogram averaging) / Resolution: 26.6 Å

Source
  • Homo sapiens (human)

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