The architecture of transmembrane and cytoplasmic juxtamembrane regions of Toll-like receptors

• Published in: Nature communications Vol. 14; no. 1; p. 1503
• Main Authors: Kornilov, F. D., Shabalkina, A. V., Lin, Cong, Volynsky, P. E., Kot, E. F., Kayushin, A. L., Lushpa, V. A., Goncharuk, M. V., Arseniev, A. S., Goncharuk, S. A., Wang, Xiaohui, Mineev, K. S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 14/1; 140/131; 38/77; 631/45/612/1237; 631/535/878/1263; 631/57/2283; 82/16; 82/29; 82/6; 82/80; 82/83; Cell Membrane - metabolism; Cytoplasm - metabolism; Domains; Functional testing; Humanities and Social Sciences; Humans; Hydrophobicity; Immune response; Immune system; Immunity, Innate; Innate immunity; Magnetic resonance spectroscopy; Mathematical models; Membranes; multidisciplinary; NMR; NMR spectroscopy; Nuclear magnetic resonance; Proteins; Receptor mechanisms; Science; Science (multidisciplinary); Structural members; TLR2 protein; TLR3 protein; TLR5 protein; TLR9 protein; Toll-Like Receptor 5 - metabolism; Toll-Like Receptor 9 - metabolism; Toll-like receptors; Toll-Like Receptors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37042-6

Toll-like receptors (TLRs) are the important participants of the innate immune response. Their spatial organization is well studied for the ligand-binding domains, while a lot of questions remain unanswered for the membrane and cytoplasmic regions of the proteins. Here we use solution NMR spectroscopy and computer simulations to investigate the spatial structures of transmembrane and cytoplasmic juxtamembrane regions of TLR2, TLR3, TLR5, and TLR9. According to our data, all the proteins reveal the presence of a previously unreported structural element, the cytoplasmic hydrophobic juxtamembrane α-helix. As indicated by the functional tests in living cells and bioinformatic analysis, this helix is important for receptor activation and plays a role, more complicated than a linker, connecting the transmembrane and cytoplasmic parts of the proteins. Toll-like receptors (TLRs) play a key role in the innate immune system. Here, Kornilov et al. resolve the 3D structures of the membrane-associated parts of four TLRs to reveal properties of the juxta-membrane domain.