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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling

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Published on: July 26, 2017

The intracellular domain of TLR2 is capable of high-affinity Zn binding: possible outcomes for the receptor

Vladislav A Lushpa^1,2, Cong Lin³, Irina A Talyzina¹

¹Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia.

|March 3, 2025

Abstract:

Toll-like receptors (TLRs) are important players in the innate immune system. Binding of pathogen-related molecules to the extracellular domains of TLRs initiates signalosome assembly, a key event in signal transduction. Despite extensive research on individual receptor domains, the mechanism of signalosome assembly remains unclear. Recent evidence suggests that the intracellular TIR domain of TLR1 binds zinc ions, with cysteines playing a pivotal role in binding and receptor activation. This study explores the zinc-binding ability of the TLR2 TIR domain (TLR2_TIR). We found that TLR2_TIR binds zinc with nanomolar affinity through its cysteine residues. Two of them, C673 and C713, are essential for receptor activation. These results suggest that zinc may be involved in the initiation of signalosome assembly.

Keywords:

NMR TIR domain TLR2, zinc Toll‐like receptor oligomerization, activation zinc binding

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