Journal:Acta Cryst D:S2059798324008210

Microcrystal electron diffraction structure of Toll-like-receptor 2 TIR domain-nucleated MyD88 TIR domain higher-order assembly

Ms Yan Li ^[1]

Molecular Tour
The structural insights gleaned from our study reveal a critical advancement in understanding how Toll-like receptors (TLRs) signal within the innate immune system. In this study, we concentrated on understanding how the TIR domain of TLR2 (TLR2TIR) interacts with the adaptor protein MyD88, a key player in the signaling pathways of the innate immune system. TLR2 typically signals as a heterodimer with TLR1 or TLR6 and recruits TIR-domain containing adaptors such as MAL and MyD88 to propagate inflammatory responses. Previous research demonstrated that the MAL TIR domain (MALTIR) could nucleate the assembly of MyD88TIR into crystalline arrays in vitro, with the structure being elucidated through microcrystal electron diffraction (MicroED). Building on this, our current work reveals that TLR2TIR, but not TLR1TIR or TLR6TIR, also induces the formation of these crystalline higher-order assemblies of MyD88TIR in vitro.

By refining our data collection methods, we successfully determined the MicroED structure of TLR2TIR-induced MyD88TIR microcrystals, achieving superior resolution (2.85 Å) and completeness (89%) compared to the previously studied MALTIR-induced MyD88TIR microcrystals. Notably, both types of assemblies showed distinct conformational differences in regions critical for signaling, such as the BB loop and CD loop, when compared to their monomeric structures. These findings suggest that TLR2TIR and MALTIR interact with MyD88 in a similar manner, promoting the unidirectional nucleation of MyD88TIR assemblies during signaling. This highlights the unique role of TLR2TIR in modulating MyD88 assembly and signaling, offering new insights into the specificity and dynamics of TLR-mediated immune responses.

References

1. ↑ Li Y, Pacoste LC, Gu W, Thygesen SJ, Stacey KJ, Ve T, Kobe B, Xu H, Nanson JD. Microcrystal electron diffraction structure of Toll-like receptor 2 TIR-domain-nucleated MyD88 TIR-domain higher-order assembly. Acta Crystallogr D Struct Biol. 2024 Sep 1;80(Pt 9):699-712. PMID:39268708 doi:10.1107/S2059798324008210