MyD88 Death-Domain Oligomerization Determines Myddosome Architecture: Implications for Toll-like Receptor Signaling

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Toll-like receptors (TLRs) initiate innate immunity upon pathogen detection.
• TLR signaling involves receptor dimerization and recruitment of adaptors like Myeloid differentiation primary response 88 (MyD88) to form the Myddosome.
• MyD88 is crucial for most TLR signaling pathways, which were thought to assemble sequentially.

Purpose of the Study:

• To investigate the in vitro self-assembly properties of MyD88.
• To determine the structural basis of MyD88 self-association.
• To understand the potential pre-assembly of MyD88 in TLR signaling.

Main Methods:

• In vitro self-assembly assays of MyD88 death domains.
• Cryoelectron microscopy (cryo-EM) at 3.1-Å resolution.
• Structural analysis of MyD88 filaments and their interaction with IRAK4.

Main Results:

• Human MyD88 death domains spontaneously form reversible helical filaments in vitro.
• The cryo-EM structure of the MyD88 filament is identical to the Myddosome complex.
• The death domain of IRAK4 binds to these filaments, reconstituting a MyD88-IRAK4 complex.

Conclusions:

• MyD88 may exist as a pre-formed scaffold intracellularly.
• This pre-formed MyD88 scaffold could be poised for rapid recruitment of IRAK kinases upon TLR activation.
• The findings challenge the model of strictly sequential Myddosome assembly.