Regulation of the Ca2+-ATPase by cholesterol: A specific or non-specific effect?
Regulation of the Ca2+-ATPase by cholesterol: A specific or non-specific effect?
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DOI：
10.3109/09687688.2015.1073382
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发表时间：
2015-01-01
影响因子：
--
通讯作者：
Thogersen, Lea
中科院分区：
文献类型：
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作者：
Autzen, Henriette Elisabeth;Siuda, Iwona;Thogersen, Lea
与其他整合膜蛋白一样，肌瘤/内质网 Ca2+-ATP 酶 (SERCA) 的活性受膜环境调节。胆固醇在内质网膜中含量较低，它有可能通过与蛋白质的直接、特异性相互作用或通过改变整体膜特性的间接相互作用来影响 SERCA 活性。有实验数据支持胆固醇介导的 SERCA 调节的两种作用模式。在当前的研究中，粗粒度分子动力学模拟用于解决混合脂质胆固醇膜如何与 SERCA 相互作用。从模拟中提取具有特定胆固醇结合模式的直接调控位点的候选者。毒胡萝卜素（SERCA 的纳摩尔抑制剂）的结合口袋已被建议作为胆固醇结合位点。然而，在模拟中，毒胡萝卜素结合袋显示出很少的胆固醇占据。毒胡萝卜素结合口袋中胆固醇的原子模拟也不支持任何特定的相互作用。目前的研究指出了胆固醇对 SERCA 活性的非特异性影响，并对用于论证特定影响的实验结果提供了另一种解释。
Like other integral membrane proteins, the activity of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) is regulated by the membrane environment. Cholesterol is present in the endoplasmic reticulum membrane at low levels, and it has the potential to affect SERCA activity both through direct, specific interaction with the protein or through indirect interaction through changes of the overall membrane properties. There are experimental data arguing for both modes of action for a cholesterol-mediated regulation of SERCA. In the current study, coarse-grained molecular dynamics simulations are used to address how a mixed lipid-cholesterol membrane interacts with SERCA. Candidates for direct regulatory sites with specific cholesterol binding modes are extracted from the simulations. The binding pocket for thapsigargin, a nanomolar inhibitor of SERCA, has been suggested as a cholesterol binding site. However, the thapsigargin binding pocket displayed very little cholesterol occupation in the simulations. Neither did atomistic simulations of cholesterol in the thapsigargin binding pocket support any specific interaction. The current study points to a non-specific effect of cholesterol on SERCA activity, and offers an alternative interpretation of the experimental results used to argue for a specific effect.