Soluble human TLR2 ectodomain binds diacylglycerol from microbial lipopeptides and glycolipids

被引:22
|
作者
Jimenez-Dalmaroni, Maximiliano J. [1 ,2 ,3 ]
Radcliffe, Catherine M. [1 ]
Harvey, David J. [1 ]
Wormald, Mark R. [1 ]
Verdino, Petra [2 ,3 ]
Ainge, Gary D. [4 ]
Larsen, David S. [4 ]
Painter, Gavin F. [5 ]
Ulevitch, Richard [6 ]
Beutler, Bruce [7 ]
Rudd, Pauline M. [1 ]
Dwek, Raymond A. [1 ]
Wilson, Ian A. [2 ,3 ]
机构
[1] Univ Oxford, Dept Biochem, Glycobiol Inst, Oxford OX1 3QU, England
[2] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA
[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
[4] Univ Otago, Dept Chem, Dunedin, New Zealand
[5] Victoria Univ Wellington, Gracefield Res Ctr, Ferrier Res Inst, Lower Hutt, New Zealand
[6] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA
[7] Scripps Res Inst, Dept Genet, La Jolla, CA 92037 USA
基金
英国惠康基金;
关键词
Diacylglycerol ligands; lipoarabinomannan; lipoteichoic acid; FSL-1; TLR2; TOLL-LIKE RECEPTOR-2; MYCOBACTERIUM-TUBERCULOSIS PHAGOSOME; LIPOTEICHOIC ACID; CRYSTAL-STRUCTURE; PHOSPHATIDYLINOSITOL MANNOSIDES; STAPHYLOCOCCUS-AUREUS; GLYCOSYLATION SITES; N-GLYCOSYLATION; ACYLATION STATE; IMMUNE-SYSTEM;
D O I
10.1177/1753425914524077
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
TLRs are key innate immune receptors that recognize conserved features of biological molecules that are found in microbes. In particular, TLR2 has been reported to be activated by different kinds of microbial ligands. To advance our understanding of the interaction of TLR2 with its ligands, the recombinant human TLR2 ectodomain (hTLR2ED) was expressed using a baculovirus/insect cell expression system and its biochemical, as well as ligand binding, properties were investigated. The hTLR2ED binds synthetic bacterial and mycoplasmal lipopeptides, lipoteichoic acid from Staphylococcus aureus, and synthetic lipoarabinomannan precursors from Mycobacterium at extracellular physiological conditions, in the absence of its co-receptors TLR1 and TLR6. We also determined that lipopeptides and glycolipids cannot bind simultaneously to hTLR2ED and that the phosphatidyl inositol mannoside 2 (Pim2) is the minimal lipoarabinomannan structure for binding to hTLR2ED. Binding of hTLR2ED to Pim4, which contains a diacylglycerol group with one of its acyl chains containing 19 carbon atoms, indicates that hTLR2ED can bind ligands with acyl chains longer than 16 carbon atoms. In summary, our data indicate that diacylglycerol is the ligand moiety of microbial glycolipids and lipoproteins that bind to hTLR2ED and that both types of ligands bind to the same binding site of hTLR2ED.
引用
收藏
页码:175 / 193
页数:19
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