Crystal structure of the mammalian lipopolysaccharide detoxifier
Crystal structure of the mammalian lipopolysaccharide detoxifier
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DOI：
10.1073/pnas.1719834115
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发表时间：
2018-01-30
影响因子：
11.1
通讯作者：
Nagar, Bhushan
中科院分区：
文献类型：
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作者：
Gorelik, Alexei;Illes, Katalin;Nagar, Bhushan
LPS是一种有效的细菌内毒素，可触发先天免疫系统。模式识别受体对LPS的正确识别需要脂质部分中典型的六个酰基链的完整互补。酰氧基酰基水解酶（AOAH）是从LPS中去除二级（酰氧基酰基连接的）脂肪酸的宿主酶，使其具有免疫惰性。这种活性对于从革兰氏阴性感染后的免疫耐受中恢复至关重要。为了了解AOAH功能的分子机制，我们确定了其晶体结构及其与LPS的复合物。底物的脂质部分被容纳在由saposin和催化结构域形成的大疏水口袋中，所述催化结构域具有插入到活性位点处的狭窄侧向疏水隧道中的二级酰基链。该酶与LPS的磷酸基团建立双链接触，但不与其寡糖部分相互作用。蛋白水解加工允许可能参与膜上底物进入的两亲性螺旋的移动。
LPS is a potent bacterial endotoxin that triggers the innate immune system. Proper recognition of LPS by pattern-recognition receptors requires a full complement of typically six acyl chains in the lipid portion. Acyloxyacyl hydrolase (AOAH) is a host enzyme that removes secondary (acyloxyacyl-linked) fatty acids from LPS, rendering it immunologically inert. This activity is critical for recovery from immune tolerance that follows Gram-negative infection. To understand the molecular mechanism of AOAH function, we determined its crystal structure and its complex with LPS. The substrate's lipid moiety is accommodated in a large hydrophobic pocket formed by the saposin and catalytic domains with a secondary acyl chain inserted into a narrow lateral hydrophobic tunnel at the active site. The enzyme establishes dispensable contacts with the phosphate groups of LPS but does not interact with its oligosaccharide portion. Proteolytic processing allows movement of an amphipathic helix possibly involved in substrate access at membranes.