The innate immune response against pathogen attacking comes through initiating downstream signal transduction by pattern recognition receptors (PRRs) to produce pro-inflammatory cytokine. Toll-like receptors (TLRs) are the central molecules of PRRs. Among five adaptor proteins (MAL, MyD88, TRAM, TRIF, and SARM1) of Toll/interleukin-1 receptor/resistance protein (TIR) domain containing TLRs, Myeloid differentiation primary response gene 88 (MyD88) is a crucial cytosolic adaptor to induce complex signalosome recruiting almost all TLRs and activate NFκB that finally arouses the immune genes.
The whole TLRs signaling system is carried out in two different pathways: MyD88 dependent and MyD88 independent (TRIF dependent). As MyD88 is associated with all the TLRs except TLR3, it is an indispensable adaptor to link with its receptors and endosomal signal transduction to form a signal by cooperative assembly formation (SCAF). Signaling pathways induce higher-order assemblies within TLRs (e. g. MAL-MyD88). Mutation and signaling disorder of MyD88 is responsible for several types of cancer, auto-immune diseases, allergies, atherosclerosis, etc. Nowadays, bat immunity is a hot topic in research fields for their extreme level of viral tolerance compare to other mammalians. Understanding the innate immunity of bats is an exciting research area to control viral pathogenicity. TLRs signaling system follows a similar pathway to induce cytokines.
MyD88 consists of TIR, intermediate domain (ID) and DD (death domain). Human MyD88TIR and DD have been solved previously. Although the oligomeric aptitude is higher in full-length MyD88, the structure of full-length is remained inconspicuous due to the difficulties of expression and purification. From fluorescence study, full-length and individual domains show distinct characteristics.
So, the contribution of both domains including the intermediate domain is our research interest to observe self-assembly of full-length MyD88, as well as functional studies, the effect of single mutagenesis.