Effect of H-Bond Donor Lipids on Phosphatidylinositol-3,4,5-Trisphosphate Ionization and Clustering
Effect of H-Bond Donor Lipids on Phosphatidylinositol-3,4,5-Trisphosphate Ionization and Clustering
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DOI：
10.1016/j.bpj.2017.10.029
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发表时间：
2018-01-09
影响因子：
3.4
通讯作者：
Kooijman, Edgar E.
中科院分区：
文献类型：
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作者：
Graber, Zachary T.;Thomas, Joseph;Kooijman, Edgar E.
磷酸肌醇，磷脂酰肌醇-3，4，5-三磷酸（PI（3，4，5）P-3），是细胞质膜内小叶中的关键信号脂质，调节包括细胞生长和迁移的多种信号通路。在这项研究中，我们研究了氢键供体脂质磷脂酰乙醇胺（PE）和磷脂酰肌醇（PI）的电荷和相行为的PI（3，4，5）P-3的影响。PE和PI可以通过氢键形成与PI（3，4，5）P-3相互作用，导致PI（3，4，5）P-3头基内的电离行为和电荷分布改变。我们使用多状态电离模型来量化改变的PI（3，4，5）P3电离行为，以获得每个磷酸基团的电离的微pKa值。PE的存在导致PI（3，4，5）P-3的初始去质子化的pKa值降低，其描述了在pH 4.0下去除剩余在磷酸单酯基团处的三个质子中的第一个质子。因此，这些微pKa值的降低导致低pH下的电荷较高。此外，电荷分布变化导致3-和5-磷酸盐上的电荷增加。在PI的存在下，PI（3，4，5）P-3的最终去质子化被延迟，导致在高pH下的较低电荷。这是由于PI和PI（3，4，5）P-3之间的氢键形成的组合，以及由于添加带负电荷的PI而增加的表面电荷。PI和PI（3，4，5）P-3之间的相互作用导致在膜内形成PI和PI（3，4，5）P-3富集结构域。这些结构域可能对PI（3，4，5）P3-信号传导具有关键影响。我们还重新评估结果为所有磷脂酰肌醇二磷酸以及PI（4，5）P-2在复杂的脂质混合物与多态电离模型。
The phosphoinositide, phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5) P-3), is a key signaling lipid in the inner leaflet of the cell plasma membrane, regulating diverse signaling pathways including cell growth and migration. In this study we investigate the impact of the hydrogen-bond donor lipids phosphatidylethanolamine (PE) and phosphatidylinositol (PI) on the charge and phase behavior of PI(3,4,5) P-3. PE and PI can interact with PI(3,4,5) P-3 through hydrogen-bond formation, leading to altered ionization behavior and charge distribution within the PI(3,4,5) P-3 headgroup. We quantify the altered PI(3,4,5) P3 ionization behavior using a multistate ionization model to obtain micro-pKa values for the ionization of each phosphate group. The presence of PE leads to a decrease in the pKa values for the initial deprotonation of PI(3,4,5) P-3, which describes the removal of the first proton of the three protons remaining at the phosphomonoester groups at pH 4.0. The decrease in these micro-pKa values thus leads to a higher charge at low pH. Additionally, the charge distribution changes lead to increased charge on the 3-and 5-phosphates. In the presence of PI, the final deprotonation of PI(3,4,5) P-3 is delayed, leading to a lower charge at high pH. This is due to a combination of hydrogen-bond formation between PI and PI(3,4,5) P-3, and increased surface charge due to the addition of the negatively charged PI. The interaction between PI and PI(3,4,5) P-3 leads to the formation of PI and PI(3,4,5) P-3-enriched domains within the membrane. These domains may have a critical impact on PI(3,4,5) P3-signaling. We also reevaluate results for all phosphatidylinositol bisphosphates as well as for PI(4,5) P-2 in complex lipid mixtures with the multistate ionization model.