Structural basis for Fc receptor recognition of immunoglobulin M

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Immunoglobulin Fc receptors regulate immune responses by interacting with antibody Fc regions.
• Fc receptor for IgM (FcμR) is crucial for B cell survival and activation.
• Understanding FcμR-IgM interaction is key to deciphering B cell signaling.

Purpose of the Study:

• To structurally elucidate the binding sites of human FcμR on the IgM pentamer.
• To understand the molecular basis of FcμR's isotype specificity for IgM.
• To explain FcμR engagement with both serum IgM and B cell receptor (BCR) IgM.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was employed to visualize the FcμR-IgM complex.
• Structural analysis identified specific binding interfaces between FcμR and IgM.

Main Results:

• Eight distinct binding sites for the FcμR immunoglobulin domain on the IgM pentamer were identified.
• One FcμR binding site overlaps with the polymeric immunoglobulin receptor (pIgR) site, but with a different binding mode.
• FcμR binding site variation and occupancy reflect IgM pentamer asymmetry and FcμR binding versatility.
• The structure explains FcμR interaction with both polymeric serum IgM and monomeric IgM BCR.

Conclusions:

• The study provides the first structural insights into FcμR binding to IgM.
• FcμR's isotype specificity is determined by its distinct binding mode to IgM.
• These findings advance our understanding of B cell regulation and immune complex clearance mediated by IgM.