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A mono-acyl phospholipid (20:1 lyso-PS) activates Toll-Like Receptor 2/6 hetero-dimer.
Chemistry and Physics of Lipids ( IF 3.4 ) Pub Date : 2020-08-12 , DOI: 10.1016/j.chemphyslip.2020.104951
Michiel L Bexkens 1 , Martin Houweling 2 , Peter C Burgers 3 , Theo M Luider 3 , Aloysius G M Tielens 4 , Jaap J van Hellemond 1
Affiliation  

Toll-like receptor 2 (TLR2) is an important pattern recognition receptor on the surface of host immune cells that binds a variety of ligands that are released by microorganisms as well as by damaged or dying host cells. According to the current concept, TLR2/1 and TLR2/6 heterodimers are activated by tri- or di-acylated ligands, respectively. However, also mono-acyl phospholipid containing lipid fractions derived from parasites, were reported to be able to activate TLR2. In order to provide conclusive evidence for the TLR2 activating capacity of mono-acyl phospholipids derived from pathogens, we developed a biosynthetic method to enzymatically convert commercially available phospholipids into several mono-acyl-phospholipid variants that were examined for their TLR2 activating capacity. These investigations demonstrated that 1-(11Z-eicosenoyl)-glycero-3-phosphoserine 20:1 (20:1 lyso-PS) is a true agonist of the TLR2/6 heterodimer and that its polar headgroup as well as the length of the acyl chain are crucial for TLR2 activation. In silico modelling further confirmed 20:1 mono-acyl PS as a ligand for TLR2/6 heterodimer, as this predicted that multiple hydrogen bonds are formed between the polar headgroup of 20:1 mono-acyl PS and amino acid residues of both TLR2 and TLR6. Future studies can now be performed to further assess the functions of 20:1 lyso-PS as an immunological mediator, because this enzymatic method enables its preparation in larger quantities than is possible by isolation from the parasite that naturally produces this compound, Schistosoma mansoni, the source of the original discovery (Van der Kleij et al., 2002).



中文翻译:

单酰基磷脂(20:1溶血PS)激活Toll样受体2/6异二聚体。

Toll样受体2(TLR2)是宿主免疫细胞表面上的一种重要模式识别受体,可与微生物,受损或垂死的宿主细胞释放的各种配体结合。根据当前的概念,TLR2 / 1和TLR2 / 6异二聚体分别被三或二酰基化的配体活化。然而,据报道,还含有衍生自寄生虫的含单酰基磷脂的脂质级分能够活化TLR2。为了为源自病原体的单酰基磷脂的TLR2活化能力提供确凿的证据,我们开发了一种生物合成方法,可将酶促水解的商业化磷脂转化为几种单酰基磷脂变异体,并对其TLR2活化能力进行了检测。在计算机模拟中进一步证实了20:1单酰基PS作为TLR2 / 6异二聚体的配体,因为这预示20:1单酰基PS的极性头基与TLR2和TLR2的氨基酸残基之间都形成了多个氢键。 TLR6。未来的研究,现在可以进行进一步评估20的功能:1溶血-PS作为免疫调节剂,因为此酶方法使其数量较多制剂比有可能通过隔离从天然产生该化合物,这种寄生虫曼氏血吸虫,原始发现的来源(Van der Kleij等,2002)。

更新日期:2020-08-21
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