Interactions of the EGFR juxtamembrane domain with PIP2-containing lipid bilayers: Insights from multiscale molecular dynamics simulations.
Interactions of the EGFR juxtamembrane domain with PIP2-containing lipid bilayers: Insights from multiscale molecular dynamics simulations.
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DOI：
10.1016/j.bbagen.2014.09.006
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Sansom MSP
中科院分区：
文献类型：
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作者：
Abd Halim KB;Koldsø H;Sansom MSP
表皮生长因子受体 (EGFR) 是受体酪氨酸激酶中特征最明确的成员，在跨哺乳动物细胞膜的信号传导中发挥着重要作用。 EGFR 近膜 (JM) 结构域参与受体激活机制，与细胞膜胞内小叶中的阴离子脂质磷脂酰肌醇 4,5-二磷酸 (PIP2) 相互作用。多尺度 MD 模拟用于表征 PIP2-JM 相互作用。对含 PIP2 和 PIP2 耗尽的脂质双层膜中的跨膜螺旋加 JM 区 (TM–JM) 二聚体 (PDB:2M20) 的模拟揭示了 JM 与 PIP2 和其他脂质的相互作用。 PIP2 与 JM 结构域 R645-R647 基序中的碱性残基形成强烈的相互作用，导致 PIP2 聚集在蛋白质周围。 PIP2 和 JM 结构域的这种结合有助于 JM-A 二聚体远离膜的稳定。突变 (R645N/R646N/R647N) 或 PIP2 缺失会导致 JM-A 二聚体变形和 JM-膜相互作用发生变化。这些模拟支持这样的观点：JM-A 结构域起始处的带正电残基通过与 PIP2 结合，将 JM-A 螺旋稳定在远离膜表面的方向，从而促进与不对称（即激活）激酶相对应的构象。这项研究表明 MD 模拟可用于表征 JM/脂质相互作用，从而有助于确定它们在受体酪氨酸激酶机制中的作用。本文是题为分子动力学最新发展的特刊的一部分。在含有 PIP2 的双层中模拟 EGFR 跨膜-近膜二聚体。 PIP2 与 JM 区域的碱性残基形成有利的相互作用。突变或 PIP2 耗尽会改变近膜与双层的相互作用。模拟支持 EGFR 激活过程中与阴离子脂质的相互作用。
The epidermal growth factor receptor (EGFR) is the best characterised member of the receptor tyrosine kinases, which play an important role in signalling across mammalian cell membranes. The EGFR juxtamembrane (JM) domain is involved in the mechanism of activation of the receptor, interacting with the anionic lipid phosphatidylinositol 4,5-bisphosphate (PIP2) in the intracellular leaflet of the cell membrane. Multiscale MD simulations were used to characterize PIP2–JM interactions. Simulations of the transmembrane helix plus JM region (TM–JM) dimer (PDB:2M20) in both PIP2-containing and PIP2-depleted lipid bilayer membranes revealed the interactions of the JM with PIP2 and other lipids. PIP2 forms strong interactions with the basic residues in the R645–R647 motif of the JM domain resulting in clustering of PIP2 around the protein. This association of PIP2 and the JM domain aids stabilization of JM-A dimer away from the membrane. Mutation (R645N/R646N/R647N) or PIP2-depletion results in deformation of the JM-A dimer and changes in JM–membrane interactions. These simulations support the proposal that the positively charged residues at the start of the JM-A domain stabilize the JM-A helices in an orientation away from the membrane surface through binding to PIP2, thus promoting a conformation corresponding to an asymmetric (i.e. activated) kinase. This study indicates that MD simulations may be used to characterise JM/lipid interactions, thus helping to define their role in the mechanisms of receptor tyrosine kinases. This article is part of a Special Issue entitled Recent developments of molecular dynamics. EGFR transmembrane–juxtamembrane dimer was simulated in PIP2-containing bilayers. PIP2 forms favourable interactions with basic residues of the JM region. Mutation or PIP2 depletion changes juxtamembrane interactions with the bilayer. Simulations support interactions with anionic lipids in activation of the EGFR.