Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering
Phosphatidylinositol 4,5-Bisphosphate Clusters the Cell Adhesion Molecule CD44 and Assembles a Specific CD44-Ezrin Heterocomplex, as Revealed by Small Angle Neutron Scattering
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DOI：
10.1074/jbc.m114.589523
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发表时间：
2015-03-06
影响因子：
4.8
通讯作者：
Bu, Zimei
中科院分区：
文献类型：
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作者：
Chen, Xiaodong;Khajeh, Jahan Ali;Bu, Zimei
细胞粘附分子CD44调节多种细胞功能，包括细胞-细胞和细胞-基质相互作用、细胞运动、迁移、分化和生长。在细胞中，CD44与膜-细胞骨架适配器蛋白Ezrin共定位，Ezrin将CD44组装受体信号复合物连接到细胞骨架肌动蛋白网络，后者组织信号事件的空间和时间定位。在这里，我们报道CD44的细胞质尾部（CD44ct）在很大程度上是紊乱的。在与信号脂质磷脂酰肌醇4,5-二磷酸（PI12）结合后，CD44ct聚集成聚集体。此外，与普遍接受的模型相反，CD44ct不直接与Ezrin的FERM结构域或全长Ezrin结合，而仅在PIP2存在时与FERM或全长Ezrin形成复合物。通过对比变化小角中子散射，我们发现PIP2介导了CD44ct与Ezrin的特异性异四聚体复合物的组装。这项研究揭示了PIP2在CD44聚集和多聚CD44- ezrin复合物组装中的作用。我们假设多价静电相互作用负责CD44簇和多聚PIP2-('D44-Ezrin)复合物的组装。
The cell adhesion molecule CD44 regulates diverse cellular functions, including cell-cell and cell-matrix interaction, cell motility, migration, differentiation, and growth. In cells, CD44 co-localizes with the membrane-cytoskeleton adapter protein Ezrin that links the CD44 assembled receptor signaling complexes to the cytoskeletal actin network, which organizes the spatial and temporal localization of signaling events. Here we report that the cytoplasmic tail of CD44 (CD44ct) is largely disordered. Upon binding to the signaling lipid phosphatidylinositol 4,5-bisphosphate (PI12), CD44ct clusters into aggregates. Further, contrary to the generally accepted model, CD44ct does not bind directly to the FERM domain of Ezrin or to the fulllength Ezrin but only forms a complex with FERM or with the full-length Ezrin in the presence of PIP2. Using contrast variation small angle neutron scattering, we show that PIP2 mediates the assembly of a specific heterotetramer complex of CD44ct with Ezrin. This study reveals the role of PIP2 in clustering CD44 and in assembling multimeric CD44-Ezrin complexes. We hypothesize that polyvalent electrostatic interactions are responsible for the assembly of CD44 clusters and the multimeric PIP2-('D44-Ezrin complexes.