Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination
Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination
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DOI：
10.1074/jbc.m504320200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Tapping, RI
中科院分区：
文献类型：
--
作者：
Omueti, KO;Beyer, JM;Tapping, RI
在10种人类toll样受体（tlr）中，TLR2似乎是独特的，它需要与其他tlr（即TLR1和TLR6）合作来介导细胞信号传导。通过重组实验，我们更精确地定义了这些人类tlr的功能。共转染TLR1和- 2的人结肠上皮细胞优先响应合成的三棕榈酰化细菌脂肽类似物(Pam（3)CSK(4)）。然而，对各种各样的脂肽衍生物的研究表明，人类TLR1和- 2的识别与修饰的半胱氨酸残基上酰基链的数量或位置并不严格相关。相反，人类TLR2和- 6只对含有二酰基甘油基团的脂肽有反应。最令人惊讶的是，我们发现二酰基化巨噬细胞激活脂肽2 （MALP-2）的R立体异构体只通过TLR6和-2激活上皮细胞，而不通过TLR1和-2。这些结果表明，这些激动剂的二酰基甘油基团的中心碳的手性是人类TLR识别的结构决定因素。对由TLR1和- 6之间的结构域交换产生的嵌合受体的检查表明，细胞外结构域的富含亮氨酸的重复序列9 - 12使这些受体能够区分结构相似的脂肽。然而，其他嵌合结构表明，仅该区域不足以产生能够与TLR2功能合作的受体。我们的研究结果支持了TLR1和TLR6在进化过程中分化以识别天然脂蛋白结构的观点，并且这种功能相对于人类受体是保守的。
Among the 10 human Toll-like receptors (TLRs), TLR2 appears to be unique in its requirement for cooperation with other TLRs, namely TLR1 and TLR6, to mediate cell signaling. Through reconstitution experiments, we have defined more precisely the function of these human TLRs. Human colonic epithelial cells cotransfected with TLR1 and - 2 preferentially respond to a synthetic tripalmitoylated bacterial lipopeptide analogue (Pam(3)CSK(4)). However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and - 2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue. Conversely, human TLR2 and - 6 exclusively respond to lipopeptides possessing a diacylglycerol group. Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and - 2 but not through TLR1 and - 2. These results suggest that the chirality of the central carbon of the diacylglycerol group of these agonists is a structural determinant for human TLR recognition. Examination of chimeric receptors, generated by domain exchange between TLR1 and - 6, has revealed that leucine-rich repeats 9 - 12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides. However, additional chimeric constructs reveal that this region alone is not sufficient to generate receptors that can functionally cooperate with TLR2. Our results support the idea that TLR1 and TLR6 diverged during evolution to differentially recognize natural lipoprotein structures and that this function has been conserved with respect to the human receptors.