Structure of a Calcium-dependent 11R-Lipoxygenase Suggests a Mechanism for Ca2+ Regulation
Structure of a Calcium-dependent 11R-Lipoxygenase Suggests a Mechanism for Ca2+ Regulation
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DOI：
10.1074/jbc.m112.343285
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发表时间：
2012-06-22
影响因子：
4.8
通讯作者：
Samel, Nigulas
中科院分区：
文献类型：
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作者：
Eek, Priit;Jaerving, Reet;Samel, Nigulas
脂氧合酶 (LOX) 是导致炎症和癌症的多种信号传导途径的关键部分。然而，各种 LOX 亚型的底物结合和变构调节机制仍然是推测性的。在这里，我们报道了来自 Gersemia fruticosa 的花生四烯酸 11R-LOX 的 2.47 埃分辨率晶体结构，这为 LOX 催化机制提供了新的线索。我们的晶体学和突变研究表明，脂肪酸的脂肪族尾部结合在具有两个潜在入口的疏水口袋中。我们推测 LOX 具有共同的 T 形底物通道结构，从而产生不同的位置特异性。提出了一种通用的变构机制，用于通过保守的阳离子桥将钙结合的活性诱导作用从膜靶向 PLAT（多囊蛋白-1/脂氧合酶/α-毒素）结构域传递到活性位点。
Lipoxygenases (LOXs) are a key part of several signaling pathways that lead to inflammation and cancer. Yet, the mechanisms of substrate binding and allosteric regulation by the various LOX isoforms remain speculative. Here we report the 2.47-angstrom resolution crystal structure of the arachidonate 11R-LOX from Gersemia fruticosa, which sheds new light on the mechanism of LOX catalysis. Our crystallographic and mutational studies suggest that the aliphatic tail of the fatty acid is bound in a hydrophobic pocket with two potential entrances. We speculate that LOXs share a common T-shaped substrate channel architecture that gives rise to the varying positional specificities. A general allosteric mechanism is proposed for transmitting the activity-inducing effect of calcium binding from the membrane-targeting PLAT (polycystin-1/lipoxygenase/alpha-toxin) domain to the active site via a conserved pi-cation bridge.