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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A_4 production
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Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A_4 production

机译：类肌动蛋白蛋白支持5-脂氧合酶活性并上调白三烯A_4的产生

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摘要

Regulation of 5-lipoxygenase (5LO) activity is a key determinant for the biosynthesis of proinflammatory leukotrienes. Coactosin-like protein (CLP) is an F-actin-binding protein that can also bind 5LO. Here, we report that CLP can up-regulate and modulate 5LO activity [formation of 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosa-tetraenoic acid (5-HPETE)], 5(S)-hydroxy-6-trans-8,11,14-cis-eicosa-tetraenoic acid (5-HETE), and 5(S)-trans-5,6-oxido-7,9-frans-11,14-cis-eicosatetraenoic acid (LTA_4) in vitro. Three findings are presented. First, CLP up-regulates Ca~(2+)-induced 5LO activity, in the absence of phosphatidylcholine (membrane). Apparently, CLP can function as a scaffold for 5LO, similar to membranes. Second, CLP gives a considerable (3-fold) increase in the amount of LTA_4 formed by 5LO, when present together with phosphatidylcholine. Third, CLP increases the ratio of 5-HETE/5-HPETE. These effects require protein interaction by Trp residues in ligand-binding loops of the 5LO β-sandwich; both binding and stimulatory effects of CLP were abolished for the mutant 5LO-W13/75/102A. In polymorphonu-clear leukocytes stimulated with Ca~(2+) ionophore, both CLP and 5LO associated with the nucleus, whereas in resting cells, CLP and 5LO were cytosolic. These findings establish CLP as a factor relevant for 5LO product formation. Functioning as a 5LO scaffold, CLP may provide a basis for the formation of 5-HETE in the cytosol of different cell types. Furthermore, in stimulated cells, CLP appears to function in a complex together with 5LO and membranes, increasing the capacity of 5LO for leukotriene biosynthesis.
机译：5-脂氧合酶（5LO）活性的调节是促炎性白三烯生物合成的关键决定因素。辅肌动蛋白样蛋白（CLP）是一种F-肌动蛋白结合蛋白，也可以结合5LO。在这里，我们报告中电可以上调和调节5LO的活性[5（S）-hydroperoxy-6-trans-8,11,14-cis-eicosa-tetraenoic acid（5-HPETE）的形成]，5（S ）-羟基-6-trans-8,11,14-顺式二十碳四烯酸（5-HETE）和5（S）-trans-5,6-oxido-7,9-frans-11,14-体外顺式二十碳四烯酸（LTA_4）。提出了三个发现。首先，在没有磷脂酰胆碱（膜）的情况下，CLP上调Ca〜（2+）诱导的5LO活性。显然，CLP可以充当5LO的支架，类似于膜。其次，当与磷脂酰胆碱一起存在时，CLP可使5LO形成的LTA_4的量显着增加（3倍）。第三，CLP增加了5-HETE / 5-HPETE的比例。这些作用需要5LOβ三明治配体结合环中的Trp残基与蛋白质相互作用。突变体5LO-W13 / 75 / 102A的CLP结合和刺激作用均被取消。在Ca〜（2+）离子载体刺激下的多形性透明白细胞中，CLP和5LO都与细胞核相关，而在静息细胞中，CLP和5LO是胞质的。这些发现将CLP确定为与5LO产品形成有关的因素。作为5LO支架，CLP可能为在不同细胞类型的细胞质中形成5-HETE提供基础。此外，在受刺激的细胞中，CLP似乎与5LO和膜一起在复合物中起作用，从而增加了5LO用于白三烯生物合成的能力。

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