Toll-like receptor signalling through macromolecular protein complexes

•The Toll-like receptor signalling proteins MyD88 and IRAK2 form a Myddosome complex.•The Toll-like receptor adaptor protein Tram dimerises and Trif forms oligomers suggesting that a “Trifosome” complex analgous to the Myddosome may form.•Inflammasome signalling also generates macromolecular protein complexes.•Macromolecular protein signalling is likely to be a common theme in Pattern Receptor signalling.

The molecular mechanisms by which pattern recognition receptors (PRRs) signal are increasingly well understood. Toll-like receptor 4 (TLR4) signals through two separate pairs of adaptor proteins Mal/MyD88 and Tram/Trif. Structural studies have revealed a common theme for PRR signalling in that their signalling proteins form large macromolecular complexes which are thought to form the active signalling complex. The first of these to be characterised was the MyD88 signalling complex Myddosome. Many questions remain unanswered however. In particular it is unclear whether these signalling complexes form within the living cell, how many of each signalling protein is within the intracellular Myddosome and whether the stoichiometry can vary in a ligand-dependent manner. In this review we will discuss what is known about the macromolecular complexes thought to be important for TLR4 signalling.