+Search query
-Structure paper
Title | Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b. |
---|---|
Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 116, Issue 24, Page 11900-11905, Year 2019 |
Publish date | Jun 11, 2019 |
Authors | Thomas H Sharp / Aimee L Boyle / Christoph A Diebolder / Alexander Kros / Abraham J Koster / Piet Gros / |
PubMed Abstract | 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 ...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 links | Proc Natl Acad Sci U S A / PubMed:31147461 / PubMed Central |
Methods | EM (subtomogram averaging) |
Resolution | 25.6 - 26.7 Å |
Structure data | EMDB-4878: EMDB-4943: EMDB-4945: |
Source |
|