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Insights Into IgM-mediated Complement Activation Based on in Situ Structures of IgM-C1-C4b

Insights Into IgM-mediated Complement Activation Based on in Situ Structures of IgM-C1-C4b

Thomas H Sharp, Aimee L Boyle, Christoph A Diebolder, Alexander Kros, Abraham J Koster, Piet Gros

Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):11900-11905.

PMID: 31147461

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-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP80295483	Complement C4 from human serum		80295-48-3	Price
IAR42411699	IgM from human serum			Price

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