The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6.
The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6.
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DOI：
10.1186/1297-9716-44-50
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发表时间：
2013-07-04
影响因子：
4.4
通讯作者：
Bryant CE
中科院分区：
文献类型：
--
作者：
Irvine KL;Hopkins LJ;Gangloff M;Bryant CE
TLR2识别细菌脂肽和脂质胆酸，并与TLR1或TLR6形成异源二聚体。TLR2在小鼠和人类中具有较好的特征，已发表的人类TLR2/1/Pam3CSK4和小鼠TLR2/6/Pam2CSK4的晶体结构。马的TLR4被一组不同于人类和小鼠的TLR4的配体激活，但对TLR2的物种差异知之甚少。因此，我们克隆了马的TLR2、TLR1和TLR6，它们与其他哺乳动物的受体序列同源性超过80%，并进行了结构功能分析。来自马和人的TLR2/1和TLR2/6对来自金黄色葡萄球菌的脂磷胆酸有剂量依赖性反应，两种受体对的EC50没有显著的物种差异。Pam2CSK4在马和人TLR2/6上的EC50相同，说明两种TLRs的氨基酸差异对配体识别没有显著影响。Pam2CSK4和Pam3CSK4在TLR2/1位点的反应存在物种差异。正如预期的那样，人类TLR2/1对Pam3CSK4的反应比Pam2CSK4具有更强的效力和疗效。然而，在马的TLR2/1中，Pam3CSK4的效力低于Pam2CSK4，两种配体具有相似的效力。分子模拟表明，大多数非保守的配体相互作用残基位于TLR2结合袋的外围和配体肽相互作用区域，这可能对配体定位产生微妙的影响。这些结果表明，TLR2/1对脂肽的识别可能存在重要的物种差异，这可能影响马如何应对细菌感染。
TLR2 recognises bacterial lipopeptides and lipoteichoic acid, and forms heterodimers with TLR1 or TLR6. TLR2 is relatively well characterised in mice and humans, with published crystal structures of human TLR2/1/Pam3CSK4 and murine TLR2/6/Pam2CSK4. Equine TLR4 is activated by a different panel of ligands to human and murine TLR4, but less is known about species differences at TLR2. We therefore cloned equine TLR2, TLR1 and TLR6, which showed over 80% sequence identity with these receptors from other mammals, and performed a structure-function analysis. TLR2/1 and TLR2/6 from both horses and humans dose-dependently responded to lipoteichoic acid from Staphylococcus aureus, with no significant species difference in EC50 at either receptor pair. The EC50 of Pam2CSK4 was the same for equine and human TLR2/6, indicating amino acid differences between the two species’ TLRs do not significantly affect ligand recognition. Species differences were seen between the responses to Pam2CSK4 and Pam3CSK4 at TLR2/1. Human TLR2/1, as expected, responded to Pam3CSK4 with greater potency and efficacy than Pam2CSK4. At equine TLR2/1, however, Pam3CSK4 was less potent than Pam2CSK4, with both ligands having similar efficacies. Molecular modelling indicates that the majority of non-conserved ligand-interacting residues are at the periphery of the TLR2 binding pocket and in the ligand peptide-interacting regions, which may cause subtle effects on ligand positioning. These results suggest that there are potentially important species differences in recognition of lipopeptides by TLR2/1, which may affect how the horse deals with bacterial infections.
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影响因子：
4.8
作者：
Omueti, KO;Beyer, JM;Tapping, RI
通讯作者：
Tapping, RI
基因转化限制了哺乳动物TLR1和TLR6的差异。
影响因子：
3.4
作者：
Kruithof EK;Satta N;Liu JW;Dunoyer-Geindre S;Fish RJ
通讯作者：
Fish RJ
影响因子：
3.2
作者：
Kurokawa, Kenji;Kim, Min-Su;Lee, Bok Luel
通讯作者：
Lee, Bok Luel
影响因子：
64.8
作者：
Horng, T;Barton, GM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
4.8
作者：
Schwandner, R;Dziarski, R;Kirschning, CJ
通讯作者：
Kirschning, CJ