Calcium Directly Regulates Phosphatidylinositol 4,5-Bisphosphate Headgroup Conformation and Recognition.
Calcium Directly Regulates Phosphatidylinositol 4,5-Bisphosphate Headgroup Conformation and Recognition.
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DOI：
10.1021/jacs.6b11760
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发表时间：
2017-03-22
影响因子：
15
通讯作者：
Coskun Ü
中科院分区：
文献类型：
--
作者：
Bilkova E;Pleskot R;Rissanen S;Sun S;Czogalla A;Cwiklik L;Róg T;Vattulainen I;Cremer PS;Jungwirth P;Coskun Ü
磷酸肌醇的协调识别和伴随的细胞内Ca 2+释放对细胞过程的几乎每个方面都至关重要，包括膜稳态、细胞分裂和生长、囊泡运输以及分泌。虽然已知Ca 2+直接影响磷酸肌醇聚集，但对其分子基础或其在细胞信号传导中的意义知之甚少。在这里，我们研究的直接相互作用的钙离子与磷脂酰肌醇4，5-二磷酸（PI（4，5）P2），质膜的主要脂质标志物。含有PI（4，5）P2的脂质体的电动势测量揭示，Ca 2+以及Mg 2+将脂质体的zeta电位降低至接近纯磷脂酰胆碱膜的背景水平。引人注目的是，默认PI（4，5）P2脂质传感器磷脂酶C δ 1普列克底物蛋白同源结构域（PLC δ1-PH）的脂质识别在Ca 2+存在下被完全抑制，而Mg 2+对100 nm脂质体没有影响，对巨大单层囊泡有适度影响。与生化数据一致，振动和频光谱和原子分子动力学模拟揭示了Ca 2+与PI（4，5）P2头基和羰基区域的结合如何导致受限的脂质头基倾斜和构象重排。我们通过钙阻断PLC δ1-PH和PI（4，5）P2之间高度特异性相互作用的能力来解释这些发现，这种相互作用编码在脂质本身的构象特性中。我们的研究表明，可切换的磷脂酰肌醇构象状态可以作为脂质识别和控制细胞信号传导机制的可能性。
The orchestrated recognition of phosphoinositides and concomitant intracellular release of Ca2+ is pivotal to almost every aspect of cellular processes, including membrane homeostasis, cell division and growth, vesicle trafficking, as well as secretion. Although Ca2+ is known to directly impact phosphoinositide clustering, little is known about the molecular basis for this or its significance in cellular signaling. Here, we study the direct interaction of Ca2+ with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), the main lipid marker of the plasma membrane. Electrokinetic potential measurements of PI(4,5)P2 containing liposomes reveal that Ca2+ as well as Mg2+ reduce the zeta potential of liposomes to nearly background levels of pure phosphatidylcholine membranes. Strikingly, lipid recognition by the default PI(4,5)P2 lipid sensor, phospholipase C delta 1 pleckstrin homology domain (PLC δ1-PH), is completely inhibited in the presence of Ca2+, while Mg2+ has no effect with 100 nm liposomes and modest effect with giant unilamellar vesicles. Consistent with biochemical data, vibrational sum frequency spectroscopy and atomistic molecular dynamics simulations reveal how Ca2+ binding to the PI(4,5)P2 headgroup and carbonyl regions leads to confined lipid headgroup tilting and conformational rearrangements. We rationalize these findings by the ability of calcium to block a highly specific interaction between PLC δ1-PH and PI(4,5)P2, encoded within the conformational properties of the lipid itself. Our studies demonstrate the possibility that switchable phosphoinositide conformational states can serve as lipid recognition and controlled cell signaling mechanisms.