Molecular mechanisms underlying inhibition of protein phosphatases by marine toxins
Molecular mechanisms underlying inhibition of protein phosphatases by marine toxins
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DOI：
10.2741/dawson
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发表时间：
1999-10-01
期刊：
影响因子：
--
通讯作者：
Holmes, Charles F. B.
中科院分区：
文献类型：
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作者：
Dawson, John F.;Holmes, Charles F. B.
蛋白质丝氨酸/苏氨酸磷酸酶构成了一类独特的酶，它们是关键的调节酶，因为它们必须中和人类细胞中数千种蛋白激酶的活性。毒性抑制剂对磷酸酶活性的不加控制的抑制会导致广泛的灾难性影响。在过去的十年中，已经鉴定出许多天然产物毒素，它们能够特异性和有效地抑制蛋白磷酸酶-1和-2A。其中包括蓝藻来源的环七肽微囊藻毒素-LR和来自甲藻来源的聚醚脂肪酸冈田酸。通过从不同来源收集的见解，这些毒素对蛋白磷酸酶-1的有效抑制的分子机制正在变得清晰起来。这些研究包括：1.毒素结构变异的比较；2.描述蛋白磷酸酶-1和-2A之间的结构差异，说明它们对冈田酸的不同敏感性；3.与微囊藻毒素-LR结合的蛋白磷酸酶-1的晶体结构测定，以及最近的4.蛋白磷酸酶-1的突变。综上所述，这些数据指向蛋白磷酸酶-1上冈田酸和微囊藻毒素-LR的共同结合部位。然而，这些数据的细节表明，每种毒素以一种微妙的不同方式结合到共同的部位，在不同程度上依赖于共同的结构相互作用。最后，来自蛋白磷酸酶-1的见解可能有助于解释其他蛋白丝氨酸/苏氨酸磷酸酶对毒素抑制的不同敏感性，这是因为该酶家族的许多成员之间具有高度的结构保守性。
The protein serine/threonine phosphatases constitute a unique class of enzymes that are critical regulatory enzymes as they must counteract the activities of thousands of protein kinases in human cells. Uncontrolled inhibition of phosphatase activity by toxic inhibitors can lead to widespread catastrophic effects. Over the past decade, a number of natural product toxins have been identified which specifically and potently inhibit protein phosphatase-1 and -2A. Among these are the cyanobacteria-derived cyclic heptapeptide microcystin-LR and the polyether fatty acid okadaic acid from dinoflagellate sources. The molecular mechanism of the potent inhibition of protein phosphatase-1 by these toxins is becoming clear through insights gathered from diverse sources. These include: 1. Comparison of structural variants of the toxins, 2. Delineating the structural differences between protein phosphatase-1 and -2A accounting for their differing sensitivity to okadaic acid, 3. Determination of the crystal structure of protein phosphatase-1 with microcystin-LR bound and, most recently, 4. Mutagenesis of protein phosphatase-1. Taken together, these data point to a common binding site on protein phosphatase-1 for okadaic acid and microcystin-LR. However, the details of these data suggest that each toxin binds to the common site in a subtly different way, relying on common structural interactions to different degrees. Finally, the insights derived from protein phosphatase-1 may help explain different sensitivities of other protein serine/threonine phosphatases to toxin inhibition due to the high degree of structural conservation among many members of this enzyme family.