Crystal structure of autotaxin and insight into GPCR activation by lipid mediators
Crystal structure of autotaxin and insight into GPCR activation by lipid mediators
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DOI：
10.1038/nsmb.1998
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发表时间：
2011-02-01
影响因子：
16.8
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Nishimasu, Hiroshi;Okudaira, Shinichi;Nureki, Osamu
自分泌运动因子（ATX，也称为Enpp2）是一种分泌的溶血磷脂酶D，其水解溶血磷脂酰胆碱以产生溶血磷脂酸（LPA），溶血磷脂酸是一种激活G蛋白偶联受体以引起各种细胞反应的脂质介质。在这里，我们报告的晶体结构的小鼠ATX单独和复杂的LPAs具有不同的酰基链长度和饱和度。这些结构揭示了多结构域架构有助于保持脂质结合口袋的结构刚性，其以不同的构象容纳相应的LPA分子。它们表明催化结构域中的环区域是Enpp家族酶的底物特异性的主要决定因素。此外，沿着生物化学和生物学数据，这些结构表明产生的LPAs通过疏水通道从活性位点递送至同源G蛋白偶联受体。
Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse ATX alone and in complex with LPAs with different acyl-chain lengths and saturations. These structures reveal that the multidomain architecture helps to maintain the structural rigidity of the lipid-binding pocket, which accommodates the respective LPA molecules in distinct conformations. They indicate that a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes. Furthermore, along with biochemical and biological data, these structures suggest that the produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel.