Transmembrane domains of TLR1 and TLR2 tend to specific heterotypic interaction

Toll-like receptors (TLRs) are participants of the innate immune system that perceive the presence of pathogens, initiating the inflammation. The key event of their activation is dimerization upon ligand recognition. Signal transduction through the membrane is mediated by transmembrane and juxtamembrane regions. However, nothing is known about the structure of the transmembrane and intracellular parts of the receptors in the activated dimeric state. Here, we investigate the dimerization of transmembrane and juxtamembrane parts (TMJMs) of TLR1 and TLR2 in lipid bilayer-containing particles using NMR spectroscopy. We found that transmembrane domains of TLR1 and TLR2 both homo- and heterodimerize, with heterodimerization being tenfold stronger compared to homotypic interaction. The heterodimer is formed via an extensive interaction interface leading to local changes in the hinge and juxtamembrane region preceding the TIR domain. We believe that TMJMs of TLR1 and TLR2 could facilitate signalosome formation affecting the TIR domain.