Structural Mechanism of Receptor-Triggered MyD88 Oligomeric Assembly in Innate Immune Signaling.

Area of Science:

• Molecular Biology
• Immunology
• Structural Biology

Background:

• Myeloid differentiation factor 88 (MyD88) is essential for Toll-like receptor (TLR) and IL-1 family signaling.
• MyD88's Toll/interleukin-1 receptor (TIR) domain mediates receptor-activated oligomerization, but its mechanism is unclear.

Purpose of the Study:

• To elucidate the structural mechanisms of TIR domain oligomerization in MyD88.
• To investigate the interaction between MyD88 TIR domains and receptor TIR domains.

Main Methods:

• Cryo-electron microscopy (Cryo-EM) to determine the structure of TIR_MyD88 oligomers.
• In vitro self-assembly assays to study TIR_MyD88 polymerization kinetics.
• High-speed atomic force microscopy (HS-AFM) to visualize dynamic oligomerization processes and receptor interactions.

Main Results:

• Tandemly arrayed TIR_MyD88 subunits assemble into antiparallel double-stranded filaments, rings, and cylindrical structures.
• Dimeric receptor TIR domains significantly accelerate TIR_MyD88 self-assembly in vitro compared to monomeric TIRs.
• HS-AFM visualized dynamic oligomerization and direct interactions between TIR_MyD88 and receptor TIRs.

Conclusions:

• MyD88 oligomerization involves the formation of complex filament and ring structures.
• Receptor dimerization likely acts as a key signal initiation step by promoting MyD88 self-assembly.
• These findings reveal a regulatory mechanism for MyD88 oligomerization in TLR signaling.