Accepted_test

The influence of zinc ions on the spatial organization and activa-tion of TIR-domains of the Toll-like receptors
by Vladislav Lushpa | Marina Goncharuk | Cong Lin | Irina Talyzina | Alezandra Luginina | Daniil Vakhrameev | Mikhail Shevtsov | Sergey Goncharuk | Alexander Arseniev | Valentin Borchevskiy | Xiaohui Wang | Konstantin Mineev | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia | Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, Chi-na | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia | Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia | Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia | Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia; Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia | Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany; JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany | Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Department of Applied Chemistry and Engineering, University of Science and Technology of China, He-fei, 230026, China | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
Abstract ID: 107
Event: BGRS-abstracts
Sections: [Sym 3] Section “Structural biology of proteins nucleic acids and membranes”

The toll-like receptor (TLR) protein family plays a crucial role in the innate immune system of humans. The human body contains 10 distinct TLRs, labeled TLR1 through TLR10. When activated, these receptors trigger the innate immune response and inflammatory processes. Research has shown that TLRs contribute to varying extents in the development of infectious diseases, autoimmune disorders, and neurodegenerative conditions.

Structurally, TLRs are type 1 transmembrane proteins characterized by large extracellular and intracellular domains connected by a single alpha-helical transmembrane segment. These receptors carry out their functions as homo- or heterodimers. Despite extensive investigation into TLRs, many unresolved questions remain regarding the structural arrangements of their intracellular domains and the mechanisms by which they become activated to initiate transduction of the immune response signaling.

Using the TIR (Toll/IL-1 Receptor) domain of TLR1 as a representative example, this study investigated the dynamics and spatial structures of this domain both in solution and crystalline states. The research demonstrated that the intracellular domains of TLRs possess metal-binding capabilities, specifically obtaining data showing their ability to bind zinc ions with nanomolar dissociation constants. Through experiments with point mutants of the TIR domains from TLRs, key amino acid residues necessary for zinc ion binding were identified within the protein sequences examined. The results further illustrate a functional analysis of TLRs, revealing the role of zinc ion binding in TLR activation and highlighting the functional significance of the previously identified crucial amino acid residues.