The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity
The Crystal Structure of Lipopolysaccharide Binding Protein Reveals the Location of a Frequent Mutation that Impairs Innate Immunity
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DOI：
10.1016/j.immuni.2013.09.005
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发表时间：
2013-10-17
期刊：
影响因子：
32.4
通讯作者：
Schumann, Ralf R.
中科院分区：
文献类型：
--
作者：
Eckert, Jana K.;Kim, Young J.;Schumann, Ralf R.
脂多糖结合蛋白(LBP)是一种在识别细菌内毒素后启动免疫反应的急性期蛋白。在这里，我们报道了小鼠LBP在2.9埃分辨率下的晶体结构。LBP与相关的杀菌/通透性增加蛋白(BPI)有几个结构差异，LBP的C-末端结构域包含一个带负电荷的凹槽和一个疏水的“苯丙氨酸核心”。一个频繁的人类LBP SNP(等位基因频率0.08)影响这一区域，可能产生一个蛋白酶裂解位点。突变蛋白与内毒素和脂肽的结合能力降低。SNP携带者在体内暴露于脂多糖后细胞因子反应降低，肺炎时细胞因子浓度降低。在一项回顾性试验中，LBP SNP与脓毒症和肺炎期间死亡率的增加有关。因此，LBP的结构完整性可能是有效对抗感染的关键，未来的患者分层可能有助于开发更好的治疗策略。
Lipopolysaccharide (LPS) binding protein (LBP) is an acute-phase protein that initiates an immune response after recognition of bacterial LPS. Here, we report the crystal structure of murine LBP at 2.9 angstrom resolution. Several structural differences were observed between LBP and the related bactericidal/permeability-increasing protein (BPI), and the LBP C-terminal domain contained a negatively charged groove and a hydrophobic "phenylalanine core." A frequent human LBP SNP (allelic frequency 0.08) affected this region, potentially generating a proteinase cleavage site. The mutant protein had a reduced binding capacity for LPS and lipopeptides. SNP carriers displayed a reduced cytokine response after in vivo LPS exposure and lower cytokine concentrations in pneumonia. In a retrospective trial, the LBP SNP was associated with increased mortality rates during sepsis and pneumonia. Thus, the structural integrity of LBP may be crucial for fighting infections efficiently, and future patient stratification might help to develop better therapeutic strategies.