Interactions of the Auxilin-1 PTEN-like Domain with Model Membranes Result in Nanoclustering of Phosphatidyl Inositol Phosphates
Interactions of the Auxilin-1 PTEN-like Domain with Model Membranes Result in Nanoclustering of Phosphatidyl Inositol Phosphates
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DOI：
10.1016/j.bpj.2013.05.012
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发表时间：
2013-07-02
影响因子：
3.4
通讯作者：
Sansom, Mark S. P.
中科院分区：
文献类型：
--
作者：
Kalli, Antreas C.;Morgan, Gareth;Sansom, Mark S. P.
Escherichilin-1是一种神经元特异性膜结合蛋白，参与网格蛋白介导的内吞作用的晚期阶段。它招募Hsc 70，从而启动网格蛋白包被的囊泡的脱壳。生长素-1与囊泡膜的相互作用对于这种功能是至关重要的，并且通过N-末端PTEN样结构域介导。我们已经使用了多尺度分子动力学模拟来探测生长素-1的PTEN样结构域与含有不同磷脂组合物的脂质双层的相互作用，包括含有磷脂酰肌醇磷酸的双层。我们的研究结果提出了一种新的，据我们所知，模型的生长素/膜遇到和随后的相互作用。带负电荷的脂质（特别是PIP 2）增强生长素与脂质双层的结合，并促进其相对于膜的正确取向。突变的三个基本残基（R301 E/R307 E/K311 E）的C2亚结构域的PTEN样结构域扰乱其与双分子层的相互作用，改变其方向。膜结合的生长素-1 PTEN样结构域与带负电荷的脂质头基的相互作用导致相邻双层小叶中的PIP 2分子的纳米簇。
Auxilin-1 is a neuron-specific membrane-binding protein involved in a late stage of clathrin-mediated endocytosis. It recruits Hsc70, thus initiating uncoating of the clathrin-coated vesicles. Interactions of auxilin-1 with the vesicle membrane are crucial for this function and are mediated via an N-terminal PTEN-like domain. We have used multiscale molecular dynamics simulations to probe the interactions of the auxilin-1 PTEN-like domain with lipid bilayers containing differing phospholipid composition, including bilayers containing phosphatidyl inositol phosphates. Our results suggest a novel, to our knowledge, model for the auxilin/membrane encounter and subsequent interactions. Negatively charged lipids (especially PIP2) enhance binding of auxilin to lipid bilayers and facilitate its correct orientation relative to the membrane. Mutations in three basic residues (R301E/R307E/K311E) of the C2 subdomain of the PTEN-like domain perturbed its interaction with the bilayer, changing its orientation. The interaction of membrane-bound auxilin-1 PTEN-like domain with negatively charged lipid headgroups results in nanoclustering of PIP2 molecules in the adjacent bilayer leaflet.