Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b.
Proc Natl Acad Sci U S A
; 116(24): 11900-11905, 2019 06 11.
Article
in En
| MEDLINE
| ID: mdl-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Complement C1
/
Complement C4
/
Immunoglobulin M
/
Complement Activation
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2019
Document type:
Article