Spatial structure of TLR4 transmembrane domain in bicelles provides the insight into the receptor activation mechanism

• Published in: Scientific reports Vol. 7; no. 1; pp. 6864 - 12
• Main Authors: Mineev, Konstantin S., Goncharuk, Sergey A., Goncharuk, Marina V., Volynsky, Pavel E., Novikova, Ekaterina V., Aresinev, Alexander S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 101/6; 631/45/612/1237; 631/535/878/1263; 64; 82; 82/16; 82/29; 82/6; 82/80; 82/83; Dimerization; Humanities and Social Sciences; Hydrophobicity; Investigations; Ligands; Lipids; Magnetic resonance spectroscopy; multidisciplinary; NMR; Nuclear magnetic resonance; Peptides; Phospholipids; Polymorphism; Protein structure; Proteins; Receptor mechanisms; Science; Science (multidisciplinary); Spectroscopy; TLR3 protein; TLR4 protein; Toll-like receptors; Transmembrane domains
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-07250-4

Toll-like receptors (TLRs) play a key role in the innate and adaptive immune systems. While a lot of structural data is available for the extracellular and cytoplasmic domains of TLRs, and a model of the dimeric full-length TLR3 receptor in the active state was build, the conformation of the transmembrane (TM) domain and juxtamembrane regions in TLR dimers is still unclear. In the present work, we study the transmembrane and juxtamembrane parts of human TLR4 receptor using solution NMR spectroscopy in a variety of membrane mimetics, including phospholipid bicelles. We show that the juxtamembrane hydrophobic region of TLR4 includes a part of long TM α-helix. We report the dimerization interface of the TM domain and claim that long TM domains with transmembrane charged aminoacids is a common feature of human toll-like receptors. This fact is analyzed from the viewpoint of protein activation mechanism, and a model of full-length TLR4 receptor in the dimeric state has been proposed.