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

Sharp, T.H.; Boyle, A.L.; Diebolder, C.A.; Kros, A.; Koster, A.; Gros, P.

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

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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., Boyle, A.L., Diebolder, C.A., Kros, A., 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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