Abstract
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.
Highlights
Toll-like receptors (TLRs) play a key role in the innate and adaptive immune systems[1]
No sign of loss of α-helical conformation is observed on the border between the TM and intracellular linker region (ICL) regions except for the chemical shifts of F654 which are close to the random coil conformation in micelles but not in bicelles
Since it is well known that the inner leaflet of cell membrane is negatively charged and TLR4-TMICL construct contains the positively charged K653 side chain immediately after the presumable transmembrane domain (TMD), we proposed that the anionic lipids could affect the behavior of the protein, and incorporated the TLR4-TMICL into the anionic DMPG/DHPC bicelles at neutral pH25
Summary
Toll-like receptors (TLRs) play a key role in the innate and adaptive immune systems[1]. Polymorphism (I602S) in the TMD of TLR1 was shown to correlate with the modified immune response to tri-acylated lipopeptides, suggesting that this region might be involved in the regulation or activation of the TLR1/2 complex. This polymorphism is associated with the Crohn’s disease[13, 19, 20]. The recent work suggests that the HR domain contains a number of potential cholesterol-binding motifs and can be utilized to transfer the receptor between the liquid crystalline membrane and ordered microdomains upon the ligand binding[16]. In order to assess the possibility of such process and look at the structural organization of the juxtamembrane and TM portions of the TLR4 receptor, we investigate here the structure of TLR4 TMD in both the absence and presence of ICL in a variety of membrane mimetics, including the phospholipid bicelles
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