Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.
Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.
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DOI：
10.1038/ncomms11248
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发表时间：
2016-04-14
影响因子：
16.6
通讯作者：
Perrakis A
中科院分区：
文献类型：
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作者：
Keune WJ;Hausmann J;Bolier R;Tolenaars D;Kremer A;Heidebrecht T;Joosten RP;Sunkara M;Morris AJ;Matas-Rico E;Moolenaar WH;Oude Elferink RP;Perrakis A
自分泌运动因子（ATX）产生脂质介质溶血磷脂酸（LPA）。ATX-LPA信号传导参与多种生物学和病理生理学过程，包括血管发生、纤维化、胆汁淤积性瘙痒和肿瘤进展。ATX具有三重活性位点，结合了亲水性沟、疏水性脂质结合口袋和功能不明确的通道。我们展示了大鼠ATX与7α-羟基胆固醇和胆盐牛磺熊去氧胆酸盐（TUDCA）结合的晶体结构，显示了通道如何选择性地结合类固醇。ATX的结构同时在隧道中携带TUDCA和在口袋中携带LPA，连同动力学分析，揭示了胆汁盐作为ATX的部分非竞争性抑制剂，从而减弱LPA受体活化。ATX-LPA信号传导与选择的类固醇（特别是天然胆汁盐）之间的这种意外的相互作用为ATX与胆汁盐的循环水平增加相关的病症的新兴关联提供了分子基础。此外，我们的研究结果表明，在使用类固醇药物的潜在临床意义。 自分泌运动因子产生生物活性脂质溶血磷脂酸以调节多种生物过程。在这里，作者确定了胆汁盐作为autotaxin活性的直接变构抑制剂的作用，表明类固醇可能作为溶血磷脂酸信号传导的调节剂。
Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs. Autotaxin generates the bioactive lipid lysophosphatidic acid to regulate diverse biological processes. Here, the authors identify a role for bile salts as direct allosteric inhibitors of autotaxin activity, suggesting that steroids may function as regulators of lysophosphatidic acid signalling.