Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China; Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands.
Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands.
Biophys J. 2018 Apr 24;114(8):1858-1868. doi: 10.1016/j.bpj.2018.02.034.
Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a signaling lipid, mediating membrane trafficking and recruitment of proteins to membranes. A key example is the PIP2-dependent regulation of the adhesion of L-selectin to the cytoskeleton adaptors of the N-terminal subdomain of ezrin-radixin-moesin (FERM). The molecular details of the mediating behavior of multivalent anionic PIP2 lipids in this process, however, remain unclear. Here, we use coarse-grained molecular dynamics simulation to explore the mechanistic details of PIP2 in the transformation, translocation, and association of the FERM/L-selectin complex. We compare membranes of different compositions and find that anionic phospholipids are necessary for both FERM and the cytoplasmic domain of L-selectin to absorb on the membrane surface. The subsequent formation of the FERM/L-selectin complex is strongly favored by the presence of PIP2, which clusters around both proteins and triggers a conformational transition in the cytoplasmic domain of L-selectin. We are able to quantify the effect of PIP2 on the association free energy of the complex by means of a potential of mean force. We conclude that PIP2 behaves as an adhesive agent to enhance the stability of the FERM/L-selectin complex and identify key residues involved. The molecular information revealed in this study highlights the specific role of membrane lipids such as PIP2 in protein translocation and potential signaling.
磷脂酰肌醇 4,5-二磷酸（PIP2）作为一种信号脂质，介导膜运输和蛋白质向膜的募集。一个关键的例子是 PIP2 依赖调节 L-选择素与 ezrin-radixin-moesin（FERM）N 端亚结构域的细胞骨架衔接蛋白的黏附。然而，该过程中多价阴离子 PIP2 脂质介导行为的分子细节仍不清楚。在这里，我们使用粗粒分子动力学模拟来探索 PIP2 在 FERM/L-选择素复合物转化、易位和缔合过程中的机制细节。我们比较了不同组成的膜，发现阴离子磷脂对于 FERM 和 L-选择素的细胞质结构域吸附在膜表面都是必需的。随后 PIP2 的存在强烈有利于 FERM/L-选择素复合物的形成，它在两种蛋白质周围聚集并引发 L-选择素细胞质结构域的构象转变。我们能够通过平均力势来量化 PIP2 对复合物缔合自由能的影响。我们的结论是，PIP2 作为一种黏附剂增强了 FERM/L-选择素复合物的稳定性，并确定了涉及的关键残基。本研究中揭示的分子信息突出了膜脂质（如 PIP2）在蛋白质易位和潜在信号转导中的特定作用。
