ИСТИНА

Toll-like receptors (TLRs) play a critical role in innate immunity as the first line of host defense. The medical and biological significance of the TLR signaling is obvious, since the disregulation of the TLR system causes various autoimmune diseases and septic shock, and some therapeutic strategies targeting TLRs have already emerged. Despite a lot of biochemical and structural data (to date, more than 40000 articles are found in PubMed upon the “TLR” request) the detailed mechanistic understanding of signal transduction remains illusive. TLRs are type I integral membrane proteins with an N-terminal extracellular ligand-binding domain, a single-span helical transmembrane (TM) region and a C-terminal cytoplasmic signaling domain. Most of the structural data are available for the extra- and intracellular domains. The only model of the dimeric full-length TLR3 receptor in the active state was build but the conformations of the TM domain and juxtamembrane regions are still unclear. Here we present the spacial structure of the TM and juxtamembrane parts of human TLR4 receptor using solution NMR spectroscopy in a variety of membrane mimetics, including phospholipid bicelles. It is thought that TM domain contains a typical stretch of approximately 20 uncharged residues, but we show that the juxtamembrane hydrophobic region of TLR4 is helical and is a part of long TM α-helix. Also we found the dimerization interface of the TM domain and claim that all TLRs are characterized by relatively long (32-35 residues) TM helices with charged aminoacids quite deep inside the membrane. This fact may be relevant for the functioning of the receptors and give a new insights into the TLRs activation mechanisms. The work was supported by the Russian Science foundation grant #14-14-00573.