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| Item Type: | Article |
|---|---|
| Title: | Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b |
| Creators Name: | Sharp, T.H. and Boyle, A.L. and Diebolder, C.A. and Kros, A. and Koster, A. and Gros, P. |
| 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 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(2) 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. |
| Keywords: | Complement, IgM, C1, Cryoelectron Tomography, Subtomogram Averaging |
| Source: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Volume: | 116 |
| Number: | 24 |
| Page Range: | 11900-11905 |
| Date: | 11 June 2019 |
| Official Publication: | https://doi.org/10.1073/pnas.1901841116 |
| PubMed: | View item in PubMed |
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