Solution NMR studies provide structural basis for endotoxin pattern recognition by the innate immune receptor CD14
Solution NMR studies provide structural basis for endotoxin pattern recognition by the innate immune receptor CD14
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DOI：
10.1016/j.bbrc.2008.01.085
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发表时间：
2008-04-04
影响因子：
3.1
通讯作者：
Jain, Nitin U.
中科院分区：
文献类型：
--
作者：
Albright, Seth;Chen, Bin;Jain, Nitin U.
在宿主先天免疫应答中，CD 14通过在部分重叠的结合位点与病原体相关分子模式（PAMP）结合，作为多种革兰氏阴性和革兰氏阳性细胞壁组分的关键模式识别受体发挥作用。为了确定CD 14残基在这种模式识别中的潜在贡献，我们已经使用溶液NMR光谱检查了三种不同的内毒素配体，脂多糖，脂磷壁酸和PGN衍生化合物，胞壁酰二肽与在巴斯德毕赤酵母中表达的sCD 14的N-15同位素标记的152个残基N-末端片段的结合。添加配体后的NMR光谱变化的映射显示，受每个配体的结合影响的残基的模式部分相似，部分不同。CD 14的特异性残基组合差异影响内毒素结合的能力的第一个直接结构观察可能有助于解释CD 14在配体识别中的广泛特异性，并为模式识别提供结构基础。观察到的光谱变化的另一个有趣的发现是，结合模式可能是动态调节的，并可能提供一种通过共同结合位点结合具有结构多样性的内毒素的机制。(C)2008年爱思唯尔公司All rights reserved.
CD14 functions as a key pattern recognition receptor for a diverse array of Gram-negative and Gram-positive cell-wall components in the host innate immune response by binding to pathogen-associated molecular patterns (PAMPs) at partially overlapping binding site(s). To determine the potential contribution of CD14 residues in this pattern recognition, we have examined using solution NMR spectroscopy, the binding of three different endotoxin ligands, lipopolysaccharide, lipoteichoic acid, and a PGN-derived compound, muramyl dipeptide to a N-15 isotopically labeled 152-residue N-terminal fragment of sCD 14 expressed in Pichia pastoris. Mapping of NMR spectral changes upon addition of ligands revealed that the pattern of residues affected by binding of each ligand is partially similar and partially different. This first direct structural observation of the ability of specific residue combinations of CD14 to differentially affect endotoxin binding may help explain the broad specificity of CD14 in ligand recognition and provide a structural basis for pattern recognition. Another interesting finding from the observed spectral changes is that the mode of binding may be dynamically modulated and could provide a mechanism for binding endotoxins with structural diversity through a common binding site. (C) 2008 Elsevier Inc. All rights reserved.